Melanocortin receptor ligands

ABSTRACT

The present invention is directed to compounds according to formula,
 
(R 2 R 3 )-A 1 - c (A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 ,
 
and pharmaceutically-acceptable salts thereof that act as ligands for one or more of the melanocortin receptors, to methods of using such compounds to treat mammals and to pharmaceutical compositions comprising said compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of pending U.S. Ser. No. 15/257,970,filed Sep. 7, 2016, which is a continuation of pending U.S. Ser. No.13/074,565, filed Mar. 29, 2011, and issued as U.S. Pat. No. 9,458,195on Oct. 4, 2016, which is a continuation application of U.S. Ser. No.11/988,533, filed May 15, 2009, and issued as U.S. Pat. No. 8,039,435 onOct. 18, 2011, which is a United States national stage filing under 35U.S.C. §371 of international (PCT) application No. PCT/US2006/026586,filed Jul. 10, 2006 and designating the U.S., which claims priority toU.S. provisional applications 60/697,779, filed Jul. 8, 2005, and60/748,850, filed Dec. 9, 2005, each of which is hereby incorporated byreference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing, which has beensubmitted in ASCII format via EFS-Web, and is hereby incorporated byreference in its entirety. The ASCII copy is named“146P2_PCT2_SeqListing.txt”, created on Jun. 4, 2007, and has the filesize of 378,000 bytes.

BACKGROUND OF THE INVENTION

The present invention is directed to peptides which are ligands of oneor more of the melanocortin receptors (MC-R), thepharmaceutically-acceptable salts thereof, to methods of using suchpeptides to treat mammals and to useful pharmaceutical compositionscomprising said peptides.

Melanocortins are a family of regulatory peptides which are formed bypost-translational processing of pro-hormone pro-opiomelanocortin (POMC;131 amino acids in length). POMC is processed into three classes ofhormones; the melanocortins, adrenocorticotropin hormone, and variousendorphins (e.g. lipotropin) (Cone, et al., Recent Prog. Horm. Res.,51:287-317, (1996); Cone et al., Ann. N.Y. Acad. Sci., 31:342-363,(1993)).

Melanocortins have been found in a wide variety of normal human tissuesincluding the brain, adrenal, skin, testis, spleen, kidney, ovary, lung,thyroid, liver, colon, small intestine and pancreas (Tatro, J. B. etal., Endocrinol. 121:1900-1907 (1987); Mountjoy, K. G. et al., Science257:1248-1251 (1992); Chhajlani, V. et al., FEBS Lett. 309:417-420(1992); Gantz, I. et al. J. Biol. Chem. 268:8246-8250 (1993) and Gantz,I. et al., J. Biol. Chem. 268:15174-15179 (1993)).

Melanocortin peptides have been shown to exhibit a wide variety ofphysiological activities including the control of behavior and memory,affecting neurotrophic and antipyretic properties, as well as affectingthe modulation of the immune system. Aside from their well known effectson adrenal cortical functions (adrenocorticotropic hormone, ACTH) and onmelanocytes (melanocyte stimulating hormone, MSH), melanocortins havealso been shown to control the cardiovascular system, analgesia,thermoregulation and the release of other neurohumoral agents includingprolactin, luteinizing hormone and biogenic amines (De Wied, D. et al.,Methods Achiev. Exp. Pathol. 15:167-199 (1991); De Wied, D. et al.,Physiol. Rev. 62:977-1059 (1982); Guber, K. A. et al., Am. J. Physiol.257:R681-R694 (1989); Walker J. M. et al., Science 210:1247-1249 (1980);Murphy, M. T. et al., Science 221:192-193 (1983); Ellerkmann, E. et al.,Endocrinol. 130:133-138 (1992) and Versteeg, D. H. G. et al., Life Sci.38:835-840 (1986)).

It has also been shown that binding sites for melanocortins aredistributed in many different tissue types including lachrymal andsubmandibular glands, pancreas, adipose, bladder, duodenum, spleen,brain and gonadal tissues as well as malignant melanoma tumors. Fivemelanocortin receptors (MC-R) have been characterized to date. Theseinclude melanocyte-specific receptor (MC1-R), corticoadrenal-specificACTH receptor (MC2-R), melacortin-3 (MC3-R), melanocortin-4 (MC4-R) andmelanocortin-5 receptor (MC5-R). All of the melanocortin receptorsrespond to the peptide hormone class of melanocyte stimulating hormones(MSH) (Cone, R. D. et al., Ann. N.Y. Acad. Sci., 680:342-363 (1993);Cone, R. D. et al., Recent Prog. Horm. Res., 51:287-318 (1996)).

MC1-R, known in the art as Melanocyte Stimulating Hormone Receptor(MSH-R), Melanotropin Receptor or Melanocortin-1 Receptor, is a 315amino acid transmembrane protein belonging to the family of G-Proteincoupled receptors. MC1-R is a receptor for both MSH and ACTH. Theactivity of MC1-R is mediated by G-proteins which activate adenylatecyclase. MC1-R receptors are found in melanocytes and corticoadrenaltissue as well as various other tissues such as adrenal gland,leukocytes, lung, lymph node, ovary, testis, pituitary, placenta, spleenand uterus. MC2-R, also called Adrenocorticotropic hormone receptor(ACTH-R), is a 297 amino acid transmembrane protein found in melanocytesand the corticoadrenal tissue. MC2-R mediates the corticotrophic effectof ACTH. In humans, MC3-R is a 360 AA protein found in brain tissue; inmice and rats MC3-R is a 323 AA protein. MC4-R is a 332 amino acidtransmembrane protein which is also expressed in brain as well asplacental and gut tissues. MC5-R is a 325 amino acid transmembraneprotein expressed in the adrenals, stomach, lung and spleen and very lowlevels in the brain. MC5-R is also expressed in the three layers ofadrenal cortex, predominantly in the aldosterone-producing zonaglomerulosa cells.

The five known melanocortin receptors differ, however, in theirfunctions. For example, MC1-R is a G-protein coupled receptor thatregulates pigmentation in response to α-MSH, a potent agonist of MC1-R.Agonism of the MC1-R receptor results in stimulation of the melanocyteswhich causes eumelanin and increases the risk for cancer of the skin.Agonism of MC1-R can also have neurological effects. Stimulation ofMC2-R activity can result in carcinoma of adrenal tissue. Recentpharmacological confirmation has established that central MC4-Rreceptors are the prime mediators of the anorexic and orexigenic effectsreported for melanocortin agonists and antagonists, respectively. Theeffects of agonism of the MC3-R and MC5-R are not yet known.

There has been great interest in melanocortin (MC-R) receptors astargets for the design of novel therapeutics to treat disorders of bodyweight such as obesity and cachexia. Both genetic and pharmacologicalevidence points toward central MC4-R receptors as the principal target(Giraudo, S. Q. et al., Brain Res., 809:302-306 (1998); Farooqi, I. S.et al., NE J Med., 348:1085-1095 (2003); MacNeil, D. J. et al., Eu. J.Pharm., 44:141-157 (2002); MacNeil, D. J. et al., Eu. J. Pharm.,450:93-109 (2002); Kask, A. et al., NeuroReport, 10:707-711 (1999)). Thecurrent progress with receptor-selective agonists and antagonistsevidences the therapeutic potential of melanocortin receptor activation,particularly MC4-R.

Agonist, antagonist or other ligand compounds activating one or moremelanocortin receptor would be useful for treating a wide variety ofindications in a subject in need thereof or at risk thereof includingacute and chronic inflammatory diseases such as general inflammation(U.S. Pat. No. 6,613,874; Catania, A. et al., Pharm. Rev., 56:1-29(2004)), inflammatory bowel disease (U.S. Pat. No. 6,713,487; Catania,A. et al., Pharm. Rev., 56:1-29 (2004)), brain inflammation (Catania, A.et al., Pharm. Rev., 56:1-29 (2004)), sepsis (U.S. Pat. No. 6,613,874;U.S. Pat. No. 6,713,487; Catania, A. et al., Pharm. Rev., 56:1-29(2004)) and septic shock (U.S. Pat. No. 6,613,874; Catania, A. et al.,Pharm. Rev., 56:1-29 (2004)); diseases with an autoimmune component suchas rheumatoid arthritis (U.S. Pat. No. 6,713,487; Catania, A. et al.,Pharm. Rev., 56:1-29 (2004)), gouty arthritis (Catania, A. et al.,Pharm. Rev., 56:1-29 (2004), Getting, S. J. et al., Curr. Opin.Investig. Drugs, 2:1064-1069 (2001)), and multiple sclerosis ((U.S. Pat.No. 6,713,487); metabolic diseases and medical conditions accompanied byweight gain such as obesity (U.S. Pat. No. 6,613,874; U.S. Pat. No.6,600,015; Fehm, H. L. et al., J. Clin. Endo. & Metab., 86:1144-1148(2001); Hansen, M. J. et al., Brain Res., 1039:137-145 (2005); Ye, Z. etal., Peptides, 26:2017-2025 (2005); Farooqi, I. S. et al., NE J Med.,348:1085-1095 (2003); MacNeil, D. J. et al., Eu. J. Pharm., 44:141-157(2002); MacNeil, D. J. et al., Eu. J. Pharm., 450:93-109 (2002); Kask,A. et al., NeuroReport, 10:707-711 (1999); Schwartz, M. W., J. Clin.Invest., 108:963-964 (2001), Gura, T., Science, 287:1738-1740 (2000),Raffin-Sanson, M. L., Eu. J. Endo., 144:207-208 (2001), Hamilton, B. S.et al., Obesity Res. 10:182-187 (2002)), feeding disorders (U.S. Pat.No. 6,720,324; Fehm, H. L. et al., J. Clin. Endo. & Metab., 86:1144-1148(2001); Pontillo, J. et al., Bioorganic & Med. Chem. Ltrs., 15:2541-2546(2005)) and Prader-Willi Syndrome (G E, Y. et al., Brain Research,957:42-45 (2002)); metabolic diseases and medical conditions accompaniedby weight loss such as anorexia (U.S. Pat. No. 6,613,874; Wisse, B. R.et al., Endo., 142:3292-3301 (2001)), bulimia (U.S. Pat. No. 6,720,324),AIDS wasting (Marsilje, T. H. et al., Bioorg. Med. Chem. Lett.,14:3721-3725 (2004); Markison, S. et al., Endocrinology, 146:2766-2773(2005)), cachexia (U.S. Pat. No. 6,613,874; Lechan, R. M. et al., Endo.,142:3288-3291 (2001); Pontillo, J. et al., Bioorganic & Med. Chem.Ltrs., 15:2541-2546 (2005)), cancer cachexia (U.S. Pat. No. 6,639,123)and wasting in frail elderly (U.S. Pat. No. 6,639,123); diabetes (U.S.Pat. No. 6,713,487) and diabetalogical related conditions andcomplications of diabetes such as retinopathy (U.S. Pat. No. 6,525,019);neoplastic proliferation (U.S. Pat. No. 6,713,487) such as skin cancer(Sturm, R. A., Melanoma Res., 12:405-416 (2002); Bastiens, M. T. et al.,Am. J. Hum. Genet., 68:884-894 (2001)), and prostate cancer (Luscombe,C. J. et al., British J. Cancer, 85:1504-1509 (2001); reproductive orsexual medical conditions such as endometriosis (U.S. Pat. No.6,713,487) and uterine bleeding in women (U.S. Pat. No. 6,613,874),sexual dysfunction (U.S. Pat. No. 6,720,324; Van der Ploeg, L. H. T. etal., PNAS, 99:11381-11386 (2002), Molinoff, P. B. et al., Ann. N.Y.Acad. Sci., 994:96-102 (2003), Hopps, C. V. et al., BJU International,92:534-538 (2003)), erectile dysfunction ((U.S. Pat. No. 6,613,874;Diamond, L. E. et al., Urology, 65:755-759 (2005), Wessells, H. et al.,Int. J. Impotence Res., 12:S74-S79 (2000), Andersson, K-E. et al., Int.J. Impotence Res., 14:S82-S92 (2002), Bertolini, A. et. al., SexualBehavior: Pharmacology and Biochemistry, Raven Press, NY, p 247-257(1975); Wessells, H. et al., Neuroscience, 118:755-762 (2003), Wessells,H. et al., Urology, 56:641-646 (2000), Shadiack, A. M. et al., Societyfor Neuroscience Abstract, (2003); Wessells, H. et al., J. Urology,160:389-393 (1998), Rosen, R. C. et al., Int. J. Impotence Res.,16:135-142 (2004), Wessells, H. et al., Peptides, 26:1972-1977 (2005))and decreased sexual response in females (U.S. Pat. No. 6,713,487;Fourcroy, J. L., Drugs, 63:1445-1457 (2003)); diseases or conditionsresulting from treatment or insult to the organism such as organtransplant rejection (U.S. Pat. No. 6,713,487; Catania, A. et al.,Pharm. Rev., 56:1-29 (2004)), ischemia and reperfusion injury (Mioni, C.et al., Eu. J. Pharm., 477:227-234 (2003); Catania, A. et al., Pharm.Rev., 56:1-29 (2004)), treatment of spinal cord injury and to acceleratewound healing (Sharma H. S. et al., Acta. Nerochir. Suppl., 86:399-405(2003); Sharma H. S., Ann. N.Y. Acad. Sci. 1053: 407-421 (2005); U.S.Pat. No. 6,525,019), as well as weight loss caused by chemotherapy,radiation therapy, temporary or permanent immobilization (Harris, R. B.et al., Physiol. Behav., 73:599-608 (2001)) or dialysis; cardiovasculardiseases or conditions such as hemorrhagic shock (Catania, A. et al.,Pharm. Rev., 56:1-29 (2004)), cardiogenic shock (U.S. Pat. No.6,613,874), hypovolemic shock (U.S. Pat. No. 6,613,874), cardiovasculardisorders (U.S. Pat. No. 6,613,874) and cardiac cachexia (Markison, S.et al., Endocrinology, 146:2766-2773 (2005); pulmonary diseases orconditions such as acute respiratory distress syndrome (U.S. Pat. No.6,350,430; Catania, A. et al., Pharm. Rev., 56:1-29 (2004)), chronicobstructive pulmonary disease (U.S. Pat. No. 6,713,487), asthma (U.S.Pat. No. 6,713,487) and pulmonary fibrosis; to enhance immune tolerance(Luger, T. A. et al., Pathobiology, 67:318-321 (1999)) and to combatassaults to the immune system such as those associated with certainallergies (U.S. Pat. No. 6,713,487) or organ transplant rejection (U.S.Pat. No. 6,713,487; Catania, A. et al., Pharm. Rev., 56:1-29 (2004));treatment of dermatological diseases and conditions such as psoriasis(U.S. Pat. No. 6,713,487), skin pigmentation depletion (U.S. Pat. No.6,713,487; Ye, Z. et al., Peptides, 26:2017-2025 (2005)), acne (Hatta,N. et al., J. Invest. Dermatol., 116:564-570 (2001); Bohm, M. et al., J.Invest. Dermatol., 118:533-539 (2002)), keloid formation (U.S. Pat. No.6,525,019) and skin cancer (Sturm, R. A., Melanoma Res., 12:405-416(2002); Bastiens, M. T. et al., Am. J. Hum. Genet., 68:884-894 (2001));behavioral, central nervous system or neuronal conditions and disorderssuch as anxiety (U.S. Pat. No. 6,720,324; Pontillo, J. et al.,Bioorganic & Med. Chem. Ltrs., 15:2541-2546 (2005)), depression (Chaki,S. et al., Peptides, 26:1952-1964 (2005), Bednarek, M. A. et al., ExpertOpinion Ther. Patents, 14:327-336 (2004); U.S. Pat. No. 6,720,324),memory and memory dysfunction (U.S. Pat. No. 6,613,874; Voisey, J. etal., Curr. Drug Targets, 4:586-597 (2003)), modulating pain perception(U.S. Pat. No. 6,613,874; Bertolini, A. et al., J. Endocrinol. Invest.,4:241-251 (1981); Vrinten, D. et al., J. Neuroscience, 20:8131-8137(2000)) and treating neuropathic pain (Pontillo, J. et al., Bioorganic &Med. Chem. Ltrs., 15:2541-2546 (2005)); conditions and diseasesassociated with alcohol consumption, alcohol abuse and/or alcoholism (WO05/060985; Navarro, M. et al., Alcohol Clin. Exp. Res., 29:949-957(2005)); and renal conditions or diseases such as the treatment of renalcachexia (Markison, S. et al., Endocrinology, 146:2766-2773 (2005)) ornatriuresis (U.S. Pat. No. 6,613,874).

Ligand compounds activating one or more melanocortin receptor would beuseful for modulating a wide variety of normalizing or homeostaticactivities in a subject in need thereof including thyroxin release (U.S.Pat. No. 6,613,874), aldosterone synthesis and release (U.S. Pat. No.6,613,874), body temperature (U.S. Pat. No. 6,613,874), blood pressure(U.S. Pat. No. 6,613,874), heart rate (U.S. Pat. No. 6,613,874),vascular tone (U.S. Pat. No. 6,613,874), brain blood flow (U.S. Pat. No.6,613,874), blood glucose levels (U.S. Pat. No. 6,613,874), bonemetabolism, bone formation or development (Dumont, L. M. et al.,Peptides, 26:1929-1935 (2005), ovarian weight (U.S. Pat. No. 6,613,874),placental development (U.S. Pat. No. 6,613,874), prolactin and FSHsecretion (U.S. Pat. No. 6,613,874), intrauterine fetal growth (U.S.Pat. No. 6,613,874), parturition (U.S. Pat. No. 6,613,874),spermatogenesis (U.S. Pat. No. 6,613,874), sebum and pheromone secretion(U.S. Pat. No. 6,613,874), neuroprotection (U.S. Pat. No. 6,639,123) andnerve growth (U.S. Pat. No. 6,613,874) as well as modulating motivation(U.S. Pat. No. 6,613,874), learning (U.S. Pat. No. 6,613,874) and otherbehaviors (U.S. Pat. No. 6,613,874).

It is, therefore, an objective of the present invention to provideligands for the melanocortin receptors which exhibit greater stabilityand selectivity for melanocortin receptors than native melanocortinreceptor ligands.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to a compound accordingformula (I):(R²R³)-A¹-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-A¹⁰-R¹wherein:

A¹ is Acc, HN—(CH₂)_(m)—C(O), L- or D-amino acid, or deleted;

A² is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;

A³ is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or deleted;

A⁴ is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or(X¹,X²,X³,X⁴,X⁵)Phe;

A⁵ is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X¹,X²,X³,X⁴,X⁵)Phe,L-Phe or D-(Et)Tyr;

A⁶ is Arg, hArg, Dab, Dap, Lys, Orn, or HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O);

A⁷ is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-1-Nal, D-2-Nal, D-Bal orD-Bip;

A⁸ is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha,HN—(CH₂)_(s)—C(O), or deleted;

A⁹ is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys;

A¹⁰ is Acc, HN—(CH₂)_(t)—C(O), L- or D-amino acid, or deleted;

R¹ is —OH, or —NH₂;

each of R² and R³ is independently for each occurrence selected from thegroup consisting of H, (C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl,(C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl,substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted(C₁-C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl,substituted aryl(C₁-C₃₀)alkyl, and substituted aryl(C₁-C₃₀)acyl;

R⁴ and R⁵ each is, independently for each occurrence, H, (C₁-C₄₀)alkyl,(C₁-C₄₀)heteroalkyl, (C₁-C₄₀)acyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl,aryl(C₁-C₄₀)alkyl, aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)alkyl,substituted (C₁-C₄₀)heteroalkyl, substituted (C₁-C₄₀)acyl, substituted(C₂-C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, substitutedaryl(C₁-C₄₀)alkyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl,or —C(NH)—NH₂;

m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7;

n is, independently for each occurrence, 1, 2, 3, 4 or 5;

s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;

t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;

X¹, X², X³, X⁴, and X⁵ each is, independently for each occurrence, H, F,Cl, Br, I, (C₁₋₁₀)alkyl, substituted (C₁₋₁₀)alkyl, (C₂₋₁₀)alkenyl,substituted (C₂₋₁₀)alkenyl, (C₂₋₁₀)alkynyl, substituted (C₂₋₁₀)alkynyl,aryl, substituted aryl, OH, NH₂, NO₂, or CN;

provided that

-   -   (I). when R⁴ is (C₁-C₄₀)acyl, aryl(C₁-C₄₀)acyl, substituted        (C₁-C₄₀)acyl, substituted aryl(C₁-C₄₀)acyl,        (C₁-C₄₀)alkylsulfonyl, or —C(NH)—NH₂, then R⁵ is H or        (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl, (C₂-C₄₀)alkenyl,        (C₂-C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl, substituted (C₁-C₄₀)alkyl,        substituted (C₁-C₄₀)heteroalkyl, substituted (C₂-C₄₀)alkenyl,        substituted (C₂-C₄₀)alkynyl, or substituted aryl(C₁-C₄₀)alkyl;    -   (II). when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted        (C₁-C₃₀)acyl, or substituted aryl(C₁-C₃₀)acyl, then R³ is H,        (C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl,        (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl,        substituted (C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl,        substituted (C₂-C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl;    -   (III). either A³ or A⁸ or both must be present in said compound;    -   (IV). when A² is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then        A⁹ is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen;    -   (V). when A² is Asp or Glu, then A⁹ is Dab, Dap, Orn, or Lys;    -   (VI). when A⁸ is Ala or Gly, then A¹ is not Nle; and    -   (VII). when A¹ is deleted, then R² and R³ cannot both be H;        or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediate foregoing formula, iswhere A¹ is A6c, Gaba, Nle, Met, Phe, D-Phe, D-2-Nal, hPhe, Chg, D-Chg,Cha, hCha, hPro, hLeu, Nip, β-hMet, or Oic;

A² is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;

A³ is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib, or deleted;

A⁴ is His;

A⁵ is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, or D-(Et)Tyr;

A⁶ is Arg, or hArg;

A⁷ is Trp, Bip, D-Trp, 1-Nal, or 2-Nal;

A⁸ is A6c, Ala, β-Ala, Gaba, Apn, or Ahx;

A⁹ is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, or Lys;

A¹⁰ is Thr, or deleted

or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group ofcompounds is where R² and R³ each is, independently, H, acyl,n-propanoyl, or n-butanoyl or a pharmaceutically acceptable saltthereof.

A more preferred compound of formula (I) is where said compound is ofthe formula:

A¹ is Acc, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu,hLeu, β-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Valor deleted;

A² is Cys, D-Cys, Pen or Asp;

A³ is Gly, Ala, β-Ala, Gaba, Aib, D-Ala, D-Abu, D-Cha, D-Ile, D-Leu,D-Tle, D-Val or deleted;

A⁴ is His or 3-Pal;

A⁵ is D-Phe, D-2-Nal or D-(Et)Tyr;

A⁶ is Arg or hArg;

A⁷ is Trp, 1-Nal, 2-Nal, Bal, Bip or D-Trp;

A⁸ is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha or deleted;

A⁹ is Cys, D-Cys, Pen or Lys;

A¹⁰ is Thr or deleted;

wherein at least one of A³ or A⁸ is deleted, but not both,

or a pharmaceutically acceptable salt thereof.

More preferred compounds of the immediately foregoing group of compoundsis where said compound is of the formula:

-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH₂;-   Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH₂;-   n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH₂;-   n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH₂;-   Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂;-   Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH₂;-   Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;-   Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;-   Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-2-Na-Arg-Trp-β-Ala-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH₂;-   Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH;-   Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;-   Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH;-   Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; or-   Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂; or    or pharmaceutically acceptable salts thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; or-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH;    or pharmaceutically acceptable salts thereof.

A more preferred compound of formula (I) is where said compound is ofthe formula:

A¹ is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe,D-Phe, hPhe, Val or deleted;

A² is Cys, Pen or Asp;

A³ is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or deleted;

A⁴ is His or 3-Pal;

A⁵ is D-Phe, D-2-Nal or D-(Et)Tyr;

A⁶ is Arg or hArg;

A⁷ is Trp, 2-Nal, Bal, Bip or D-Trp;

A⁸ is Gly, Ala, β-Ala, Gaba, Apn, Ahx, or deleted;

A⁹ is Cys, D-Cys, Pen or Lys;

A¹⁰ is Thr or deleted;

each of R² and R³ is independently selected from the group consisting ofH or acyl;

or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂;-   Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-3β-Ala-D-Cys)-Thr-NH₂;-   Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH₂;-   Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH₂;-   Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH₂;-   Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;-   Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-3Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;-   Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH₂;-   Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH₂;-   Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂; or-   Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;    or a pharmaceutically acceptable salt thereof.

A more preferred compound of formula (I) is where said compound is ofthe formula:

A¹ is Arg, D-Arg, hArg or D-hArg;

or a pharmaceutically acceptable salt thereof.

A more preferred compound of the immediately foregoing group ofcompounds is where said compound is of the formula:

A² is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;

A³ is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib, or deleted;

A⁴ is His;

A⁵ is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, or D-(Et)Tyr;

A⁶ is Arg, or hArg;

A⁷ is Trp, Bip, D-Trp, 1-Nal, or 2-Nal;

A⁸ is A6c, Ala, β-Ala, Gaba, Apn, or Ahx;

A⁹ is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, or Lys;

A¹⁰ is Thr, or deleted;

or a pharmaceutically acceptable salt thereof.

A more preferred compound of the immediately foregoing group ofcompounds is where R² and R³ each is, independently, H, acyl,n-propanoyl, or n-butanoyl or a pharmaceutically acceptable saltthereof.

A more preferred compound of the immediately foregoing group ofcompounds is where said compound is of the formula:

A² is Cys or Asp;

A³ is D-Ala or deleted;

A⁴ is His;

A⁵ is D-Phe or D-2-Nal;

A⁶ is Arg;

A⁷ is Trp;

A⁸ is Ala, Gaba or deleted;

A⁹ is Cys, Pen or Lys;

A¹⁰ is deleted;

or a pharmaceutically acceptable salt thereof.

A more preferred compound of the immediately foregoing group ofcompounds is where R² and R³ each is, independently, H or acyl; or apharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂;-   Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂; or-   Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;    or pharmaceutically acceptable salts thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; or-   Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;    or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;    or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;    or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;    or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention is directed to a compound accordingformula (II):(R²R³)-A¹-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-NH₂wherein:

A¹ is Nle or deleted;

A² is Cys or Asp;

A³ is Glu or D-Ala;

A⁴ is His;

A⁵ is D-Phe;

A⁶ is Arg;

A⁷ is Trp, 2-Nal or Bal;

A⁸ is Gly, Ala, D-Ala, β-Ala, Gaba or Apn;

A⁹ is Cys or Lys;

each of R² and R³ is independently selected from the group consisting ofH or (C₁-C₆)acyl;

provided that

-   -   (I). when R² is (C₁-C₆)acyl, then R³ is H; and    -   (II). when A² is Cys, then A⁹ is Cys,        or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing group of compounds is acompound of the formula:

-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂;-   Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂;-   Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH₂;-   Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂;-   Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; or-   Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH₂;    or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula (I) or formula (II) is eachof the compounds that are specifically enumerated herein below in theExamples section of the present disclosure, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier or diluent.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, wherein said compound is a selective melanocortin-4 receptoragonist.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, wherein said compound is a selective melanocortin 4 receptoragonist with a functional activity characterized by an EC₅₀ at least15-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 1 receptor, the human melanocortin 3 receptor andthe human melanocortin 5 receptor.

In yet another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, wherein said compound is a selective melanocortin 4 receptoragonist with a functional activity characterized by an EC₅₀ at least17-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 3 receptor, an EC₅₀ at least 90-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 3 receptor, an EC₅₀ at least 200-fold more selective forthe human melanocortin 4 receptor than for the human melanocortin 5receptor, or an EC₅₀ at least 3000-fold more selective for the humanmelanocortin 4 receptor than for the human melanocortin 5 receptor.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating an acute or chronic inflammatory disease ormedical condition such as general inflammation, inflammatory boweldisease, brain inflammation, sepsis and septic shock.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a disease or medical condition with anautoimmune component such as rheumatoid arthritis, gouty arthritis andmultiple sclerosis.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a metabolic disease or medical conditionaccompanied by weight gain such as obesity, feeding disorders andPrader-Willi Syndrome. In a further aspect, the disease or conditiontreated is obesity. In yet a further aspect, the disease or conditiontreated is a feeding disorder.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for decreasing food intake, for decreasing body weightor a combination thereof. In a preferred embodiment, the presentinvention provides a pharmaceutical composition comprising an effectiveamount of a compound of formula (I) as defined hereinabove, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier or diluent, which is useful fordiminishing food intake, decreasing body weight, or a combinationthereof, wherein the active ingredient is one or more of the followingcompounds: Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂,Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂,Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂,Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂,Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂,D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂,Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂ orAc-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂. In yet anotherpreferred embodiment, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)as defined hereinabove, or a pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier or diluent, which isuseful for diminishing food intake, decreasing body weight, or acombination thereof, wherein the active ingredient isAc-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂. In yet another preferredembodiment, the present invention provides a pharmaceutical compositioncomprising an effective amount of a compound of formula (I) as definedhereinabove, or a pharmaceutically acceptable salt thereof, togetherwith a pharmaceutically acceptable carrier or diluent, which is usefulfor diminishing food intake, decreasing body weight, or a combinationthereof, wherein the active ingredient isAc-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂. In yet anotherpreferred embodiment, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)as defined hereinabove, or a pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier or diluent, which isuseful for diminishing food intake, decreasing body weight, or acombination thereof, wherein the active ingredient isAc-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically-acceptable carrier ordiluent, which is useful for decreasing appetite without compromisingbody weight. In yet another aspect, the present invention provides apharmaceutical composition comprising an effective amount of a compoundof formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof, together with apharmaceutically-acceptable carrier or diluent, useful for decreasingfood consumption while increasing body weight.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a metabolic disease or medical conditionaccompanied by weight loss such as anorexia, bulimia, AIDS wasting,cachexia, cancer cachexia and wasting in frail elderly. In a furtheraspect, the disease or condition treated is anorexia. In a furtheraspect, the disease or condition treated is bulimia. In a furtheraspect, the disease or condition treated is AIDS wasting or wasting infrail elderly. In a further aspect, the disease or condition treated iscachexia or cancer cachexia.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a neoplastic disease or medical conditionsuch as skin cancer and cancer cachexia.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a reproductive or sexual medical conditionsuch as endometriosis, uterine bleeding, sexual dysfunction, erectiledysfunction and decreased sexual response in females.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a disease or medical condition resultingfrom treatment or insult to an organism such as organ transplantrejection, ischemia and reperfusion injury, wounding and spinal cordinjury, and weight loss due to a medical procedure selected from thegroup consisting of chemotherapy, radiation therapy, temporary orpermanent immobilization and dialysis.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a cardiovascular disease or medicalcondition such as hemorrhagic shock, cardiogenic shock, hypovolemicshock, cardiovascular disorders and cardiac cachexia.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a pulmonary disease or medical conditionsuch as acute respiratory distress syndrome, pulmonary fibrosis, chronicobstructive pulmonary disease and asthma.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for enhancing immune tolerance and treating allergies.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier ordiluent, useful for treating a dermatological disease or medicalcondition such as psoriasis, skin pigmentation depletion, acne andkeloid formation.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically-acceptable carrier ordiluent, useful for treating a behavioral or central nervous system orneuronal disease or medical condition such as anxiety, depression,memory dysfunction and neuropathic pain.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically-acceptable carrier ordiluent, useful for treating a renal disease or medical condition suchas renal cachexia and natriuresis.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically-acceptable carrier ordiluent, useful for modulating ovarian weight, placental development,prolactin secretion, FSH secretion, intrauterine fetal growth,parturition, spermatogenesis, thyroxin release, aldosterone synthesisand release, body temperature, blood pressure, heart rate, vasculartone, brain blood flow, blood glucose levels, sebum secretion, pheromonesecretion, motivation, learning and behavior, pain perception,neuroprotection and nerve growth.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically-acceptable carrier ordiluent, useful for modulating bone metabolism, bone formation and bonedevelopment.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula (I)or formula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically-acceptable carrier ordiluent, useful for inhibiting alcohol consumption, for reducing alcoholconsumption, for treating alcoholism, or for treating alcohol abuse. Ina further aspect, the compound of the composition useful for inhibitingalcohol consumption, for reducing alcohol consumption, for treatingalcoholism, or for treating alcohol abuse is a selective melanocortin 4receptor agonist. In yet a further aspect, the compound of thecomposition useful for inhibiting alcohol consumption is a selectivemelanocortin 4 receptor agonist, or a pharmaceutically acceptable saltthereof, with a functional activity characterized by an EC₅₀ at least15-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 1 receptor, the human melanocortin 3 receptor andthe human melanocortin 5 receptor. In yet another aspect, the compoundof the composition useful for inhibiting alcohol consumption is aselective melanocortin 4 receptor agonist, or a pharmaceuticallyacceptable salt thereof, with a functional activity characterized by anEC₅₀ at least 17-fold more selective for the human melanocortin 4receptor than for the human melanocortin 3 receptor, an EC₅₀ at least90-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 3 receptor, an EC₅₀ at least 200-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 5 receptor, or an EC₅₀ at least 3000-fold more selectivefor the human melanocortin 4 receptor than for the human melanocortin 5receptor.

In another aspect, the present invention provides the use of atherapeutically effective amount of a melanocortin 4 receptor agonistcompound of formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament useful for inhibiting alcohol consumption, for reducingalcohol consumption, for treating alcoholism, or for treating alcoholabuse in a subject in need of such treatment.

In yet another aspect, the present invention provides a method ofeliciting an agonist or an antagonist effect from a melanocortinreceptor in a subject in need thereof which comprises administering tosaid subject an effective amount of a compound of formula (I) or formula(II) as defined hereinabove, or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides a method of elicitingan agonist or an antagonist effect from a melanocortin receptor in asubject in need thereof which comprises administering to said subject aneffective amount of a compound of formula (I) or formula (II) as definedhereinabove, or a pharmaceutically acceptable salt thereof, wherein saidcompound is a selective melanocortin 4 receptor agonist.

In another aspect, the present invention provides a method of elicitingan agonist or an antagonist effect from a melanocortin receptor in asubject in need thereof which comprises administering to said subject aneffective amount of a compound of formula (I) or formula (II) as definedhereinabove, or a pharmaceutically acceptable salt thereof, wherein saidcompound is a selective melanocortin 4 receptor agonist with afunctional activity characterized by an EC₅₀ at least 15-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 1 receptor, the human melanocortin 3 receptor and the humanmelanocortin 5 receptor.

In yet another aspect, the present invention provides a method ofeliciting an agonist or an antagonist effect from a melanocortinreceptor in a subject in need thereof which comprises administering tosaid subject an effective amount of a compound of formula (I) or formula(II) as defined hereinabove, or a pharmaceutically acceptable saltthereof, wherein said compound is a selective melanocortin 4 receptoragonist with a functional activity characterized by an EC₅₀ at least17-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 3 receptor, an EC₅₀ at least 90-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 3 receptor, an EC₅₀ at least 200-fold more selective forthe human melanocortin 4 receptor than for the human melanocortin 5receptor, or an EC₅₀ at least 3000-fold more selective for the humanmelanocortin 4 receptor than for the human melanocortin 5 receptor.

In another aspect, the present invention provides a method of treatingan acute or chronic inflammatory disease or medical condition such asgeneral inflammation, inflammatory bowel disease, brain inflammation,sepsis and septic shock by eliciting an agonist or antagonist effectfrom a melanocortin receptor by administering an effective amount of acompound of formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating adisease or medical condition with an autoimmune component such asrheumatoid arthritis, gouty arthritis and multiple sclerosis byeliciting an agonist or antagonist effect from a melanocortin receptorby administering an effective amount of a compound of formula (I) orformula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof.

In another aspect, the present invention provides a method of treating ametabolic disease or medical condition accompanied by weight gain suchas obesity, feeding disorders and Prader-Willi Syndrome by eliciting anagonist or antagonist effect from a melanocortin receptor byadministering an effective amount of a compound of formula (I) orformula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof. In a further aspect of the foregoing method, the diseaseor condition treated is obesity. In yet a further aspect of theforegoing method, the disease or condition treated is a feedingdisorder.

In another aspect, the present invention provides a method of decreasingfood intake, decreasing body weight or a combination thereof, byeliciting an agonist or antagonist effect from a melanocortin receptorby administering an effective amount of a compound of formula (I) orformula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof. In a preferred embodiment, the present invention providesa method of decreasing food intake, decreasing body weight or acombination thereof, by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, whereinsaid compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂,Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂,Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂,Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂,Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂,D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂,Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂, orAc-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂. In another preferredembodiment, the present invention provides a method of decreasing foodintake, decreasing body weight or a combination thereof, by eliciting anagonist or antagonist effect from a melanocortin receptor byadministering an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, wherein said compound isAc-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂. In another preferredembodiment, the present invention provides a method of decreasing foodintake, decreasing body weight or a combination thereof, by eliciting anagonist or antagonist effect from a melanocortin receptor byadministering an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, wherein said compound isAc-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂. In another preferredembodiment, the present invention provides a method of decreasing foodintake, decreasing body weight or a combination thereof, by eliciting anagonist or antagonist effect from a melanocortin receptor byadministering an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, wherein said compound isAc-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂.

In another aspect, the present invention provides a method of decreasingappetite without compromising body weight by administering an effectiveamount of a compound of formula (I) or formula (II) as definedhereinabove, or a pharmaceutically acceptable salt thereof. In anotheraspect, the present invention provides a method of decreasing foodconsumption while increasing body weight by administering an effectiveamount of a compound of formula (I) or formula (II) as definedhereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating ametabolic disease or medical condition accompanied by weight loss suchas anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia andwasting in frail elderly by eliciting an agonist or antagonist effectfrom a melanocortin receptor by administering an effective amount of acompound of formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof. In a further aspect, theforegoing method is used to treat anorexia. In a further aspect, theforegoing method is used to treat bulimia. In a further aspect, theforegoing method is used to treat AIDS wasting or wasting in frailelderly. In a further aspect, the foregoing method is used to treatcachexia or cancer cachexia.

In another aspect, the present invention provides a method of treating aneoplastic disease or medical condition such as skin cancer and cancercachexia by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating areproductive or sexual medical condition such as endometriosis, uterinebleeding, sexual dysfunction, erectile dysfunction and decreased sexualresponse in females by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating adisease or medical condition resulting from treatment or insult to anorganism such as organ transplant rejection, ischemia and reperfusioninjury, wounding and spinal cord injury, and weight loss due to amedical procedure selected from the group consisting of chemotherapy,radiation therapy, temporary or permanent immobilization and dialysis byeliciting an agonist or antagonist effect from a melanocortin receptorby administering an effective amount of a compound of formula (I) orformula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof.

In another aspect, the present invention provides a method of treating acardiovascular disease or medical condition such as hemorrhagic shock,cardiogenic shock, hypovolemic shock, cardiovascular disorders andcardiac cachexia by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating apulmonary disease or medical condition such as acute respiratorydistress syndrome, pulmonary fibrosis, chronic obstructive pulmonarydisease and asthma by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of enhancingimmune tolerance or treating allergies by eliciting an agonist orantagonist effect from a melanocortin receptor by administering aneffective amount of a compound of formula (I) or formula (II) as definedhereinabove, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treatingdermatological disease or medical condition such as psoriasis, skinpigmentation depletion, acne and keloid formation by eliciting anagonist or antagonist effect from a melanocortin receptor byadministering an effective amount of a compound of formula (I) orformula (II) as defined hereinabove, or a pharmaceutically acceptablesalt thereof.

In another aspect, the present invention provides a method of treating abehavioral or central nervous system or neuronal disease or medicalcondition such as anxiety, depression, memory dysfunction andneuropathic pain by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating arenal disease or medical condition such as renal cachexia andnatriuresis by eliciting an agonist or antagonist effect from amelanocortin receptor by administering an effective amount of a compoundof formula (I) or formula (II) as defined hereinabove, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of modulatinga normalizing or homeostatic activity such as ovarian weight, placentaldevelopment, prolactin secretion, FSH secretion, intrauterine fetalgrowth, parturition, spermatogenesis, thyroxin release, aldosteronesynthesis and release, body temperature, blood pressure, heart rate,vascular tone, brain blood flow, blood glucose levels, sebum secretion,pheromone secretion, motivation, learning and behavior, pain perception,neuroprotection and nerve growth by eliciting an agonist or antagonisteffect from a melanocortin receptor by administering an effective amountof a compound of formula (I) or formula (II) as defined hereinabove, ora pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of modulatinga normalizing or homeostatic activity such as bone metabolism, boneformation and bone development by eliciting an agonist or antagonisteffect from a melanocortin receptor by administering an effective amountof a compound of formula (I) or formula (II) as defined hereinabove, ora pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of inhibitingalcohol consumption, for reducing alcohol consumption, for treatingalcoholism, or for treating alcohol abuse by eliciting an agonist orantagonist effect from a melanocortin receptor by administering aneffective amount of a compound of formula (I) or formula (II) as definedhereinabove, or a pharmaceutically acceptable salt thereof. In a furtheraspect of the foregoing method, the compound is a selective melanocortin4 receptor agonist. In yet a further aspect of the immediately foregoingmethod, the compound of the composition useful for inhibiting alcoholconsumption is a selective melanocortin 4 receptor agonist, or apharmaceutically acceptable salt thereof, with a functional activitycharacterized by an EC₅₀ at least 15-fold more selective for the humanmelanocortin 4 receptor than for the human melanocortin 1 receptor, thehuman melanocortin 3 receptor and the human melanocortin 5 receptor. Inyet another aspect of the foregoing method, the compound of thecomposition useful for inhibiting alcohol consumption is a selectivemelanocortin 4 receptor agonist, or a pharmaceutically acceptable saltthereof, with a functional activity characterized by an EC₅₀ at least17-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 3 receptor, an EC₅₀ at least 90-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 3 receptor, an EC₅₀ at least 200-fold more selective forthe human melanocortin 4 receptor than for the human melanocortin 5receptor, or an EC₅₀ at least 3000-fold more selective for the humanmelanocortin 4 receptor than for the human melanocortin 5 receptor.

In a further aspect, the present invention provides the use of atherapeutically effective amount of a melanocortin 4 receptor agonist orantagonist compound according formula (I) or formula (II) as definedhereinabove, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament useful to treat a disease and/or medicalcondition selected from the group consisting of acute and chronicinflammatory diseases such as general inflammation, inflammatory boweldisease, brain inflammation, sepsis and septic shock; diseases with anautoimmune component such as rheumatoid arthritis, gouty arthritis andmultiple sclerosis; metabolic diseases and medical disorders accompaniedby weight gain such as obesity, feeding disorders and Prader-WilliSyndrome; metabolic diseases and medical disorders accompanied by weightloss such as anorexia, bulimia, AIDS wasting, cachexia, cancer cachexiaand wasting in frail elderly; diabetes, diabetalogical relatedconditions and complications of diabetes such as retinopathy; neoplasticproliferation such as skin cancer and prostate cancer; reproductive orsexual medical conditions such as endometriosis and uterine bleeding inwomen, sexual dysfunction, erectile dysfunction and decreased sexualresponse in females; diseases or conditions resulting from treatment orinsult to the organism such as organ transplant rejection, ischemia andreperfusion injury, spinal cord injury and wounding, as well as weightloss caused chemotherapy, radiation therapy, temporary or permanentimmobilization or dialysis; cardiovascular diseases or conditions suchas hemorrhagic shock, cardiogenic shock, hypovolemic shock,cardiovascular disorders and cardiac cachexia; pulmonary diseases orconditions such as acute respiratory distress syndrome, chronicobstructive pulmonary disease, asthma and pulmonary fibrosis; to enhanceimmune tolerance and to combat assaults to the immune system such asthose associated with certain allergies or organ transplant rejection;treatment of dermatological diseases and conditions such as psoriasis,skin pigmentation depletion, acne, keloid formation and skin cancer;behavioral, central nervous system and neuronal disorders such asanxiety, depression, memory dysfunction, and neuropathic pain; and renalconditions or diseases such as the treatment of renal cachexia andnatriuresis.

In a further aspect, the present invention provides the use of atherapeutically effective amount of a melanocortin 4 receptor agonist orantagonist compound according formula (I) or formula (II) as definedhereinabove, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament useful to modulate normalizing orhomeostatic activities such as ovarian weight, placental development,prolactin secretion, FSH secretion, intrauterine fetal growth,parturition, spermatogenesis, thyroxin release, aldosterone synthesisand release, body temperature, blood pressure, heart rate, vasculartone, brain blood flow, blood glucose levels, sebum secretion, pheromonesecretion, motivation, learning and behavior, pain perception,neuroprotection, nerve growth, bone metabolism, bone formation and bonedevelopment.

It will be appreciated that therapeutic interventions addressing bothnormal physiological and pathophysiological processes which utilize themelanocortin receptors are also contemplated.

Additional objects, advantages, and features of the present inventionwill become apparent from the following description and appended claims,taken in conjunction with the accompanying drawings.

The compounds of formulae (I) or (II) are ligands for at least one ofthe melanocortin receptors (MC1-R, MC2-R, MC3-R, MC4-R and MC5-R) and aselection thereof were tested for their ability to act as a ligand inthe in vitro assay described below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A: Mean difference in food consumed from vehicle in fasted rats 6hours after administration of 100 nmole/Kg of selected compounds.

FIG. 1B. Mean difference in food consumed from vehicle in fasted rats 6hours after administration of 500 nmole/Kg of selected compounds.

FIG. 2A. Cumulative difference in mean food intake from vehicle in ratsafter administration of various concentrations of Compound A.

FIG. 2B. Cumulative mean body weight difference from vehicle in ratsafter administration of various concentrations of Compound A.

FIG. 3A. Cumulative difference in mean food intake from vehicle in ratsafter administration of selected compounds.

FIG. 3B. Cumulative mean body weight difference from vehicle in ratsafter administration of selected compounds.

FIG. 4A. Cumulative difference in mean food intake from vehicle in ratsafter administration of selected compounds.

FIG. 4B. Cumulative mean body weight difference from vehicle in ratsafter administration of selected compounds.

DETAILED DESCRIPTION OF THE INVENTION

The nomenclature used to define the peptides is that typically used inthe art wherein the amino group at the N-terminus appears to the leftand the carboxyl group at the C-terminus appears to the right. Where theamino acid has isomeric forms, it is the L form of the amino acid thatis represented unless otherwise explicitly indicated. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs. Also, all publications, Patentapplications, Patents and other references mentioned herein areincorporated by reference.

Nomenclature and Abbreviations

Symbol Meaning Abu α-aminobutyric acid Ac acyl group Acc1-amino-1-cyclo(C₃-C₉)alkyl carboxylic acid A3c1-amino-1-cyclopropanecarboxylic acid A4c1-amino-1-cyclobutanecarboxylic acid A5c1-amino-1-cyclopentanecarboxylic acid A6c1-amino-1-cyclohexanecarboxylic acid Aha 7-aminoheptanoic acid Ahx6-aminohexanoic acid Aib α-aminoisobutyric acid Ala or A alanine β-Alaβ-alanine Apn 5-aminopentanoic acid (HN—(CH2)₄—C(O) Arg or R argininehArg homoarginine Asn or N asparagine Asp or D aspartic acid Bal3-benzothienylalanine Bip 4,4′-biphenylalanine, represented by thestructure

Bpa 4-benzoylphenylalanine 4-Br-Phe 4-bromo-phenylalanine Chaβ-cyclohexylalanine hCha homo-cyclohexylalanine Chg cydohexylglycine Cysor C cysteine hCys homocysteine Dab 2,4-diaminobutyric acid Dap2,3-diaminopropionic acid Dip β,β-diphenylalanine Doc8-amino-3,6-dioxaoctanoic acid with the structure of:

2-Fua β-(2-furyl)-alanine Gaba 4-aminobutyric acid Gln or Q glutamineGlu or E glutamic acid Gly or G glycine His or H histidine 3-Hyptrans-3-hydroxy-L-proline, i.e., (2S, 3S)-3-hydroxypyrrolidine-2-carboxylic acid 4-Hyp 4-hydroxyproline, i.e., (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid Ile or I isoleucine Leu or Lleucine hLeu homoleucine Lys or K lysine Met or M methionine β-hMetβ-homomethionine 1-Nal β-(1-naphthyl)alanine: 2-Nalβ-(2-naphthyl)alanine Nip nipecotic acid Nle norleucine Oicoctahydroirtdole-2-carboxylic acid Orn ornithine 2-Palβ-(2-pyridiyl)alanine 3-Pal β-(3-pyridiyl)alanine 4-Palβ-(4-pyridiyl)alanine Pen penicillamine Phe or F phenylalanine hPhehomophenylalanine Pro or P proline hPro homoproline Ser or S serine Tletert-Leucine Taz β-(4-thiazolyl)alanine 2-Thi β-(2-thienyl)alanine 3-Thiβ-(3-thienyl)alanine Thr or T threonine Trp or W tryptophan Tyr or Ytyrosine D-(Et)Tyr has a structure of

Val or V valine

Certain other abbreviations used herein are defined as follows:

-   Boc: tert-butyloxycarbonyl-   Bzl: benzyl-   DCM: dichloromethane-   DIC: N, N-diisopropylcarbodiimide-   DIEA: diisopropylethyl amine-   Dmab:    4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl)amino}benzyl-   DMAP: 4-(dimethylamino)pyridine-   DMF dimethylformamide-   DNP: 2,4-dinitrophenyl-   Fm: fluorenylmethyl-   Fmoc: fluorenylmethyloxycarbonyl-   For: formyl-   HBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   cHex cyclohexyl-   HOAT: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HOBt: 1-hydroxy-benzotriazole-   MBHA 4-methylbenzhydrylamine-   Mmt: 4-methoxytrityl-   NMP: N-methylpyrrolidone-   O-tBu oxy-tert-butyl-   Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-   PyBroP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate-   tBu: tert-butyl-   TIS: triisopropylsilane-   TOS: tosyl-   Trt trityl-   TFA: trifluoro acetic acid-   TFFH: tetramethylfluoroforamidinium hexafluorophosphate-   Z: benzyloxycarbonyl

Unless otherwise indicated, with the exception of the N-terminal aminoacid, all abbreviations (e.g. Ala) of amino acids in this disclosurestand for the structure of —NH—C(R)(R′)—CO—, wherein R and R′ each is,independently, hydrogen or the side chain of an amino acid (e.g., R═CH₃and R′═H for Ala), or R and R′ may be joined to form a ring system.

For the N-terminal amino acid, the abbreviation stands for the structureof:

The designation “NH₂” in e.g.,Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂, indicates that theC-terminus of the peptide is amidated.Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys), or alternativelyAc-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH, indicates that theC-terminus is the free acid.

“-c(Cys-Cys)-” or “-cyclo(Cys-Cys)-” denotes the structure:

“-c(Cys-Pen)-” or “-cyclo(Cys-Pen)-” denotes the structure:

“-c(Asp-Lys)-” or “-cyclo(Asp-Lys)-” denotes the structure:

“Acyl” refers to R″—C(O)—, where R″ is H, alkyl, substituted alkyl,heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl,aryl, alkylaryl, or substituted alklyaryl, and is indicated in thegeneral formula of a particular embodiment as “Ac”.

“Alkyl” refers to a hydrocarbon group containing one or more carbonatoms, where multiple carbon atoms if present are joined by singlebonds. The alkyl hydrocarbon group may be straight-chain or contain oneor more branches or cyclic groups.

“Hydroxyalkyl” refers to an alkyl group wherein one or more hydrogenatoms of the hydrocarbon group are substituted with one or more hydroxyradicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.

“Substituted alkyl” refers to an alkyl wherein one or more hydrogenatoms of the hydrocarbon group are replaced with one or moresubstituents selected from the group consisting of halogen, (i.e.,fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH₂, —NHCH₃,—NO₂, and —C₁₋₂₀ alkyl, wherein said —C₁₋₂₀ alkyl optionally may besubstituted with one or more substituents selected, independently foreach occurrence, from the group consisting of halogens, —CF₃, —OCH₃,—OCF₃, and —(CH₂)₀₋₂₀—COOH. In different embodiments 1, 2, 3 or 4substituents are present. The presence of —(CH₂)₀₋₂₀—COOH results in theproduction of an alkyl acid. Non-limiting examples of alkyl acidscontaining, or consisting of, —(CH₂)₀₋₂₀—COOH include 2-norbornaneacetic acid, tert-butyric acid, 3-cyclopentyl propionic acid, and thelike.

The term “halo” encompasses fluoro, chloro, bromo and iodo.

“Heteroalkyl” refers to an alkyl wherein one of more of the carbon atomsin the hydrocarbon group is replaced with one or more of the followinggroups: amino, amido, —O—, —S— or carbonyl. In different embodiments 1or 2 heteroatoms are present.

“Substituted heteroalkyl” refers to a heteroalkyl wherein one or morehydrogen atoms of the hydrocarbon group are replaced with one or moresubstituents selected from the group consisting of halogen, (i.e.,fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH₂, —NHCH₃,—NO₂, and —C₁₋₂₀ alkyl, wherein said —C₁₋₂₀ alkyl optionally may besubstituted with one or more substituents selected, independently foreach occurrence, from the group consisting of halogens, —CF₃, —OCH₃,—OCF₃, and —(CH₂)₀₋₂₀—COOH. In different embodiments 1, 2, 3 or 4substituents are present.

“Alkenyl” refers to a hydrocarbon group made up of two or more carbonswhere one or more carbon-carbon double bonds are present. The alkenylhydrocarbon group may be straight-chain or contain one or more branchesor cyclic groups.

“Substituted alkenyl” refers to an alkenyl wherein one or more hydrogensare replaced with one or more substituents selected from the groupconsisting of halogen (i.e., fluorine, chlorine, bromine, and iodine),—OH, —CN, —SH, —NH₂, —NHCH₃, —NO₂, and —C₁₋₂₀ alkyl, wherein said —C₁₋₂₀alkyl optionally may be substituted with one or more substituentsselected, independently for each occurrence, from the group consistingof halogens, —CF₃, —OCH₃, —OCF₃, and —(CH₂)₀₋₂₀—COOH. In differentembodiments 1, 2, 3 or 4 substituents are present.

“Aryl” refers to an optionally substituted aromatic group with at leastone ring having a conjugated pi-electron system, containing up to threeconjugated or fused ring systems. Aryl includes carbocylic aryl,heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5- or6-membered ring. Preferred atoms for a heterocyclic aryl are one or moresulfur, oxygen, and/or nitrogen. Non-limiting examples of aryl includephenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole,9-anthracene, and the like. Aryl substituents are selected from thegroup consisting of —C₁₋₂₀ alkyl, —C₁₋₂₀ alkoxy, halogen (i.e.,fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH₂, —NO₂,—C₁₋₂₀ alkyl substituted with halogens, —CF₃, —OCF₃, and—(CH₂)₀₋₂₀—COOH. In different embodiments the aryl contains 0, 1, 2, 3,or 4 substituents.

“Alkylaryl” refers to an “alkyl” joined to an “aryl”.

The term “(C₁-C₁₂)hydrocarbon moiety” encompasses alkyl, alkenyl andalkynyl and in the case of alkenyl and alkynyl there is C₂-C₁₂.

As used herein, the term “normalizing” functions or activities refers tothose types of functions which may be considered to be involved innormal body function or homeostasis of an organism. Such functionsinclude but are not limited to activities and functions affecting bodytemperature, blood pressure, heart rate, vascular tone, brain bloodflow, blood glucose levels and the like.

As used herein, compounds which are considered to be “selective” for aparticular melanocortin receptor are those compounds with a functionalactivity characterized by an EC₅₀ at least about 2-fold, at least about5-fold, at least about 10-fold, at least about 15-fold, at least about17-fold, at least about 90-fold, at least about 200-fold, at least about3000-fold or at least about 10,000-fold, or even greater, selectivityfor any melanocortin receptor as compared to any other melanocortinreceptor. For example, a selective melanocortin 4 receptor agonist ofthe invention exhibits a functional activity characterized by an EC₅₀ atleast about 15-fold more selective for the human melanocortin 4 receptorthan for the human melanocortin 1 receptor, the human melanocortin 3receptor and the human melanocortin 5 receptor. Also for example, aselective melanocortin 4 receptor agonist of the invention exhibits afunctional activity characterized by an EC₅₀ at least 17-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 3 receptor.

Synthesis

The peptides of this invention can be prepared by standard solid phasepeptide synthesis. See, e.g., Stewart, J. M., et al., Solid PhaseSynthesis (Pierce Chemical Co., 2d ed. 1984). The substituents R² and R³of the above generic formula may be attached to the free amine of theN-terminal amino acid by standard methods known in the art. For example,alkyl groups, e.g., (C₁-C₃₀)alkyl, may be attached using reductivealkylation. Hydroxyalkyl groups, e.g., (C₁-C₃₀)hydroxyalkyl, may also beattached using reductive alkylation wherein the free hydroxyl group isprotected with a t-butyl ester. Acyl groups, e.g., COE¹, may be attachedby coupling the free acid, e.g., E¹COOH, to the free amine of theN-terminal amino acid by mixing the completed resin with 3 molarequivalents of both the free acid and diisopropylcarbodiimide inmethylene chloride for one hour. If the free acid contains a freehydroxyl group, e.g., p-hydroxyphenylpropionic acid, then the couplingshould be performed with an additional 3 molar equivalents of HOBt.

When R¹ is —NH₂, the synthesis of the peptide starts with an Fmoc-aminoacid which is coupled to the Rink Amide MBHA resin. If R¹ is —OH, thesynthesis of the peptide starts with a Fmoc-amino acid which is coupledto Wang resin.

In the synthesis of a peptide of this invention containing A6c and/orAib, the coupling time is 2 hours for these residues and the residueimmediately following them.

The following examples describe synthetic methods for making a peptideof this invention, which methods are well-known to those skilled in theart. Other methods are also known to those skilled in the art. Theexamples are provided for the purpose of illustration and are not meantto limit the scope of the present invention in any manner.

EXAMPLES Example 1: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂

The title peptide was synthesized on an Advanced ChemTech model 396®multiple peptide synthesizer (Louisville, Ky. 40228) usingFluorenylmethyloxycarbonyl (Fmoc) chemistry. A Rink Amide4-methylbenzylhydrylamine (MBHA) resin (Novabiochem®, San Diego, Calif.)with substitution of 0.58 mmol/g was used. The Fmoc amino acids(Novabiochem®, CA and Chem-Impex®, IL) used were Fmoc-Nle-OH,Fmoc-Cys(Trt)-OH, Fmoc-D-Ala-OH, Fmoc-His(Trt)-OH, Fmoc-D-Phe-OH,Fmoc-Arg(Pbf)-OH, and Fmoc-Trp(Boc)-OH. The synthesis was carried out ona 0.035 mmol scale. The Fmoc groups were removed by treatment with 25%piperidine in N,N-dimethylformamide (DMF) for 30 minutes. In eachcoupling step, the Fmoc amino acid (10 eq, 0.35 mmol), N,N-diisopropylcarbodiimide (DIC) (10 eq, 0.35 mmol), and1-hydroxy-benzotriazole (HOBt) (10 eq, 0.35 mmol) were used in DMF (1.4mL). After washing with DMF, double-coupling was performed with theFmoc-amino acid (10 eq, 0.35 mmol),2-(1-H-benzotriazole-1-yl)-1,1,2,3-tetramethyluroniumhexafluorophosphate (HBTU) (8 eq, 0.28 mmol), HOBT (10 eq, 0.35 mmol),and diisopropylethyl amine (DIEA) (20 eq, 0.7 mmol) in DMF (1.26 mL).The ACT 396® multiple peptide synthesizer was programmed to perform thefollowing reaction cycle: (1) washing with DMF, (2) removing Fmocprotecting group with 25% piperidine in DMF for 30 minutes, β) washingwith DMF, (4) coupling with Fmoc amino acid in the presence of DIC andHOBT for 1 hour, (5) washing with DMF, (6) double-coupling with the sameFmoc amino acid in step 4 in the presence of HBTU, HOBt, and DIEA for 1hour. The resin was coupled successively according to the sequence ofthe title peptide. After the peptide chain was assembled and the lastFmoc-protecting group was removed, the resin was washed completely byusing DMF and dichloromethane (DCM).

To cleave the title peptide, the resin was treated with a solution (1.5mL) of TFA, H₂O and triisopropylsilane (TIS) (v/v/v: 90/6.2/3.8) for 2hours at room temperature. The resin was filtered off and the filtratewas poured into 30 mL of ether. The precipitate was collected bycentrifugation. This crude product was dissolved in water (˜7 mL) andthe pH of the aqueous solution was adjusted to ˜7.5 by adding 2NNH₄HCO₃. The solution was opened to the air for 72 hours at roomtemperature. The resulting crude product was purified on a reverse-phasepreparative HPLC system with a column (4×43 cm) of C₁₈ DYNAMAX-100® A⁰(Varian®, Walnut Creek, Calif.). The column was eluted overapproximately 1 hour using a linear gradient of 85% A:15% B to 30% A:70%B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. Thefractions were checked by analytical HPLC and those containing pureproduct were pooled and lyophilized to dryness to give 10.3 mg (27%yield) of a white solid. Purity was assayed using HPLC and found to beapproximately 88%. Electro-spray ionization mass spectrometry (ESI-MS)analysis gave the molecular weight at 1073.6 (in agreement with thecalculated molecular weight of 1074.3).

Example 2: Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂

The title peptide was synthesized on an Applied Biosystems® (FosterCity, Calif.) model 430A peptide synthesizer which was modified to doaccelerated Boc-chemistry solid phase peptide synthesis. See Schnolzer,et al., Int. J. Peptide Protein Res., 40:180 (1992).4-methylbenzhydrylamine (MBHA) resin (Peninsula®, Belmont, Calif.) withthe substitution of 0.91 mmol/g was used. The Boc amino acids(Novabiochem®, San Diego, Calif. and Chem-Impex®, Wood Dale, Ill.) usedwere: Boc-Cha-OH, Boc-Asp(OFm)-OH, Boc-His(DNP)-OH, Boc-D-Phe-OH,Boc-Arg(Tos)-OH, Boc-Trp(For)-OH, Boc-Gaba-OH, and Boc-Lys(Fmoc)-OH. Thesynthesis was carried out on a 0.20 mmol scale. The Boc groups wereremoved by treatment with 100% TFA for 2×1 minute. Boc amino acids (2.5mmol) were pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mLof DMF and were coupled without prior neutralization of thepeptide-resin TFA salt. Coupling times were 5 minutes.

At the end of the assembly ofBoc-Asp(OFm)-His(DNP)-D-Phe-Arg(Tos)-Trp(For)-Gaba-Lys(Fmoc)-MBHA, thepeptide-resin was transferred into a reaction vessel on a shaker. Theresin was treated twice with 25% piperidine in DMF for 15 minutes persession, washed with DMF, and shaken withbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (6 eq,0.3 mmol), DIEA (1 mL), and 4-(dimethylamino)pyridine (DMAP) (24 mg) inDMF (2 mL) for 12 hours. After washing with DMF, the resin was treatedtwice with 100% TFA for 2 minutes per treatment, washed with DMF andDCM, and then dried under reduced pressure. One fourth of thepeptide-resin (0.05 mmol) was used for the next coupling with Boc-Cha-OH(10 eq, 0.5 mmol) in the presence of HBTU (9 eq, 0.45 mmol) and DIEA(0.25 mL) in DMF for 10 minutes. After the deprotection with 100% TFA intwo sessions lasting approximately 2 minutes each, the peptide-resin wasthen washed with DMF. The final capping step was done by shaking theresin with acetic anhydride (40 eq, 2.0 mmol) and DIEA (20 eq, 1.0 mmol)in DMF for 1 hour. After washing with DMF, the resin was treated twicewith a solution of 20% mercaptoethanol/10% DIEA in DMF, each treatmentlasting approximately 30 minutes, to remove the DNP group on theHistidine side chain. The formyl group on the side chain of Tryptophanwas removed by shaking with a solution of 15% ethanolamine/15% water/70%DMF twice for 30 minutes per shaking. The peptide-resin was washed withDMF and DCM and dried under reduced pressure. The final cleavage wasdone by stirring the peptide-resin in 10 mL of HF containing 1 mL ofanisole and dithiothreitol (30 mg) at 0° C. for 75 minutes. HF wasremoved by a flow of nitrogen. The residue was washed with ether (6×10mL) and extracted with 4N HOAc (6×10 mL).

The peptide mixture in the aqueous extract was purified on reverse-phasepreparative high pressure liquid chromatography (HPLC) using a reversephase VYDAC® C₁₈ column (Nest Group®, Southborough, Mass.). The columnwas eluted with a linear gradient (10% to 50% of solution B over 40minutes) at a flow rate of 10 mL/minute (Solution A=water containing0.1% TFA; Solution B=acetonitrile containing 0.1% of TFA). Fractionswere collected and checked on analytical HPLC. Those containing pureproduct were combined and lyophilized to dryness. 5.1 mg of a whitesolid was obtained. Yield was 8.9%. Purity was 94.5% based on analyticalHPLC analysis. Electro-spray mass spectrometer (MS(ES))S analysis gavethe molecular weight at 1148.5 (in agreement with the calculatedmolecular weight of 1148.3).

Other peptides of the invention can be prepared by a person of ordinaryskill in the art using synthetic procedures analogous to those disclosedgenerally hereinabove and/or to those disclosed specifically in theforegoing examples, as were the compounds depicted in Tables 1A and 1B.

Other peptides of the invention can be prepared by a person of ordinaryskill in the art using synthetic procedures analogous to those disclosedgenerally hereinabove and/or to those disclosed specifically in theforegoing examples, as were the compounds depicted in Tables 1A and 1B.

The following examples can be made according to the appropriateprocedures described above:

-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH₂;-   Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂;-   Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH₂;-   n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH₂;-   n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH₂;-   Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂;-   Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂;-   Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH₂;-   Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH₂;-   Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂;-   Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH₂;-   Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂;-   Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;-   Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;-   Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-2-Na-Arg-Trp-β-Ala-Lys)-NH₂;-   Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH₂;-   Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH₂;-   Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH;-   D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH;-   Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;-   Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH;-   Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH;-   Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;-   Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;-   Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂;-   Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂;-   Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂;-   Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂;-   Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂;-   Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂; and-   Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH.

Other peptides of the invention can be prepared by a person of ordinaryskill in the art using synthetic procedures analogous to those disclosedgenerally hereinabove and/or to those disclosed specifically in theforegoing examples, as were the compounds depicted in Tables 1A and 1B.

TABLES 1A and 1B—Molecular Weight and Purity for Selected Embodiments

TABLE 1A Calculated Experimental Molecular Molecular Compound WeightWeight Purity Ac-Nle-c(Asp-His-D-Phe-Arg- 1095.27 1095.2 96.4Trp-β-Ala-Lys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg- 1149.36 1149.05 96Trp-A6c-Lys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg- 1116.38 1115.8 98Trp-Ahx-Cys)-NH₂ D-Phe-c(Cys-His-D-Phe-Arg-Trp- 1167.38 1167.3 99Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-Phe-Arg-Trp- 1167.38 1167.5 93β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-Phe-Arg-Trp- 1181.41 1181.9 99Gaba-D-Cys)-Thr-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg- 1102.35 1103 99Trp-Apn-Cys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg- 1123.32 1123.9 99Trp-Apn-Lys)-NH₂ Ac-A6c-c(Asp-His-D-Phe-Arg- 1121.31 1121.2 93Trp-Gaba-Lys)-NH₂ Ac-D-2-Nal-c(Asp-His-D-Phe- 1193.37 1193.2 92.6Arg-Trp-Gaba-Lys)-NH₂ Ac-Cha-c(Asp-His-D-Phe-Arg- 1149.36 1149.4 94.5Trp-Gaba-Lys)-NH₂; Ac-Nle-c(Asp-His-D-Phe-Arg- 1109.3 1109.2 91.5Trp-Gaba-Lys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1074.3 1074.6 98.3Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-β-Ala-His-D-Phe- 1074.3 1074.4 91Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-Gaba-His-D-Phe- 1088.32 1088.4 93Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-Aib-His-D-Phe- 1088.32 1088.4 80Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-Gly-His-D-Phe- 1060.27 1060.4 90Arg-Trp-Cys)-NH₂ Ac-Nle-c(D-Cys-Ala-His-D-Phe- 1074.3 1074.4 93Arg-Trp-Cys)-NH₂ Ac-Nle-c(D-Cys-D-Ala-His-D- 1074.3 1074.4 81Phe-Arg-Trp-Cys)-NH₂ Ac-Nle-c(D-Cys-β-Ala-His-D- 1074.3 1074.4 92Phe-Arg-Trp-Cys)-NH₂ Ac-Nle-c(D-Cys-Gaba-His-D-Phe- 1088.32 1088.4 94Arg-Trp-Cys)-NH₂ Ac-Nle-c(D-Cys-Aib-His-D-Phe- 1088.32 1088.4 91Arg-Trp-Cys)-NH₂ Ac-Nle-c(D-Cys-Gly-His-D-Phe- 1060.27 1060.4 96Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1074.3 1074.4 66Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(Cys-β-Ala-His-D-Phe- 1074.3 1074.2 94Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(Cys-Gaba-His-D-Phe- 1088.32 1088.2 93Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(Cys-Aib-His-D-Phe- 1088.32 1088.4 90Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(Cys-Gly-His-D-Phe- 1060.27 1060.4 91Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(D-Cys-Ala-His-D-Phe- 1074.3 1074.4 65Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(D-Cys-D-Ala-His-D- 1074.3 1074.2 93Phe-Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(D-Cys-β-Ala-His-D- 1074.3 1074.4 92Phe-Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(D-Cys-Gaba-His-D-Phe- 1088.32 1088.4 90Arg-Trp-D-Cys)-NH₂ Ac-Nle-c(D-Cys-Aib-His-D-Phe- 1088.32 1088 95Arg-Trp-D-Cys)-NH₂ Ac-Oic-c(Asp-His-D-Phe-Arg- 1147.35 1147.4 97.5Trp-Gaba-Lys)-NH₂ Ac-Chg-c(Asp-His-D-Phe-Arg- 1135.33 1135.1 99Trp-Gaba-Lys)-NH₂ Ac-hCha-c(Asp-His-D-Phe-Arg- 1163.39 1163.4 99Trp-Gaba-Lys)-NH₂ Ac-D-Cha-c(Asp-His-D-Phe-Arg- 1149.36 1149.2 99Trp-Gaba-Lys)-NH₂ Ac-Nip-c(Asp-His-D-Phe-Arg- 1107.28 1107 98.9Trp-Gaba-Lys)-NH₂ Ac-hPro-c(Asp-His-D-Phe-Arg- 1107.28 1107.4 99Trp-Gaba-Lys)-NH₂ Ac-hLeu-c(Asp-His-D-Phe-Arg- 1123.32 1123.2 99Trp-Gaba-Lys)-NH₂ Ac-D-hCha-c(Asp-His-D-Phe- 1163.39 1163.6 94Arg-Trp-Gaba-Lys)-NH₂ Ac-Phe-c(Asp-His-D-Phe-Arg- 1143.31 1143.3 96.9Trp-Gaba-Lys)-NH₂ Ac-D-Phe-c(Asp-His-D-Phe-Arg- 1143.31 1143.3 96.5Trp-Gaba-Lys)-NH₂ Ac-D-Chg-c(Asp-His-D-Phe-Arg- 1135.33 1135.4 99Trp-Gaba-Lys)-NH₂ n-Butyryl-Cha-c(Asp-His-D-Phe- 1177.41 1177.5 88.6Arg-Trp-Gaba-Lys)-NH₂ Ac-hPhe-c(Asp-His-D-Phe-Arg- 1157.34 1157.2 70Trp-Gaba-Lys)-NH₂ Ac-β-hMet-c(Asp-His-D-Phe- 1141.36 1141.2 89Arg-Trp-Gaba-Lys)-NH₂ Ac-Gaba-c(Asp-His-D-Phe-Arg- 1081.24 1080.9 92.5Trp-Gaba-Lys)-NH₂ Ac-Cha-c(Asp-His-D-Phe-Arg-D- 1135.33 1135.2 85Trp-Ala-Lys)-NH₂ Ac-hCha-c(Asp-His-D-Phe-Arg- 1149.36 1149.1 87D-Trp-Ala-Lys)-NH₂ Ac-Leu-c(Asp-His-D-Phe-Arg-D- 1095.27 1095.4 98.6Trp-Ala-Lys)-NH₂ Ac-hLeu-c(Asp-His-D-Phe-Arg- 1109.3 1109.2 93.8D-Trp-Ala-Lys)-NH₂ Ac-Phe-c(Asp-His-D-Phe-Arg-D- 1129.29 1129.2 81.9Trp-Ala-Lys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1095.27 1095.3 97Trp-D-Ala-Lys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1095.27 1095.3 82Trp-β-Ala-Lys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1109.3 1109.1 99Trp-Gaba-Lys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1137.35 1137.4 98Trp-Aha-Lys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg-D- 1123.32 1123.3 97.3Trp-Apn-Lys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1102.35 1102 99Trp-Apn-Cys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1088.32 1087.8 97Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1116.38 1116.2 99Trp-Ahx-Cys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1074.3 1073.8 99.9Trp-β-Ala-Cys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg-D- 1074.3 1073.8 99.9Trp-D-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-2- 1124.36 1123.6 96.1Nal-Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-2- 1135.38 1134.5 99.1Nal-Arg-2-Nal-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-2- 1135.38 1134.6 94.8Nal-Arg-1-Nal-Cys)-NH₂ nButanoyl-Nle-c(Cys-D-Ala-His- 1113.37 1112.695.7 D-Phe-Arg-2-Nal-Cys)-NH₂ nButanoyl-Nle-c(Cys-D-Ala-His- 1102.351101.5 99.9 D-Phe-Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1085.321084.4 97.7 Arg-2-Nal-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1085.321084.5 96.6 Arg-1-Nal-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1091.351090.4 96.2 Arg-Bal-Cys)-NH₂ Ac-Nle-c(Cys-D-Glu-His-D-Phe- 1132.331131.5 99.9 Arg-Trp-Cys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg- 1095.27 1094.699.9 Trp-D-Ala-Lys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-2- 1141.41 1140.5 95.6Nal-Arg-Bal-Cys)-NH₂ Ac-Nle-c(Pen-D-Ala-His-D-Phe- 1102.35 1101.6 99.9Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1102.35 1101.6 99.9Arg-Trp-Pen)-NH₂ Ac-Nle-c(Pen-D-Ala-His-D-Phe- 1130.4 1129.6 99.9Arg-Trp-Pen)-NH₂ D-Phe-c(Cys-His-D-Phe-hArg- 1181.41 1181.7 96.9Trp-β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-(Et)Tyr-Arg- 1211.43 1211.797.1 Trp-β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-Phe-Arg-Bip- 1204.441204.6 99 β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-(Et)Tyr-hArg- 1225.461225.7 97 Trp-β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-Phe-hArg- 1218.471218.8 99 Bip-β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-(Et)Tyr-hArg-1262.52 1263 99 Bip-β-Ala-D-Cys)-Thr-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe-1131.35 1131.2 96.8 Arg-Trp-Gly-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe-1145.37 1145.3 96.4 Arg-Trp-D-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe-1145.37 1145.2 98.2 Arg-Trp-β-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe-1159.4 1159.2 95.1 Arg-Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe-1173.43 1173.3 96.8 Arg-Trp-Apn-Cys)-NH₂ Nle-c(Cys-His-D-Phe-Arg-Trp-1060.31 1060.3 98.5 Apn-Cys)-NH₂ Ac-Nle-c(Asp-D-Ala-His-D-Phe- 1095.271094.7 96.2 Arg-Trp-Lys)-NH₂ Ac-Nle-c(Asp-D-Ala-His-D-Phe- 1112.321111.7 96.5 Arg-Bal-Lys)-NH₂ Ac-c(Cys-Glu-His-D-Phe-Arg- 1090.25 1089.699.9 Trp-Ala-Cys)-NH₂ Ac-c(Cys-Glu-His-D-Phe-Arg-2- 1101.27 1100.6 98.3Nal-Ala-Cys)-NH₂ Ac-c(Cys-D-Ala-His-D-Phe-Arg- 1032.22 1031.5 95.2Trp-Ala-Cys)-NH₂ Ac-c(Cys-D-Ala-His-D-Phe-Arg- 1043.24 1042.5 95.62-Nal-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1144.39 1144.6 95.3Arg-Trp-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1145.37 1144.6 97.3Arg-Trp-β-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1158.41 1158.6 96.5Arg-Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1103.33 1103 99.9Arg-Trp-Pen)-OH Ac-Nle-c(Cys-D-Abu-His-D-Phe- 1088.32 1087.6 99.9Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Val-His-D-Phe- 1102.35 1101.7 99.9Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Ile-His-D-Phe- 1116.38 1115.7 99.9Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Leu-His-D-Phe- 1116.38 1115.8 97.4Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Tle-His-D-Phe- 1116.38 1115.5 96.5Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Cha-His-D-Phe- 1156.44 1155.6 96.4Arg-Trp-Cys)-NH₂ Ac-Nle-c(Pen-His-D-Phe-Arg- 1116.38 1115.7 95Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg- 1116.38 1115.5 99.9Trp-Gaba-Pen)-NH₂ Ac-Nle-c(Pen-His-D-Phe-Arg- 1144.43 1144 99.9Trp-Gaba-Pen)-NH₂ Ac-Leu-c(Cys-His-D-Phe-Arg- 1088.32 1088 96.7Trp-Gaba-Cys)-NH₂ Ac-Cha-c(Cys-His-D-Phe-Arg- 1128.39 1128.4 95.8Trp-Gaba-Cys)-NH₂ Ac-Ile-c(Cys-His-D-Phe-Arg-Trp- 1088.32 1088.4 95Gaba-Cys)-NH₂ Ac-Phe-c(Cys-His-D-Phe-Arg- 1122.34 1122 95.2Trp-Gaba-Cys)-NH₂ Ac-Val-c(Cys-His-D-Phe-Arg- 1074.3 1074.6 95.4Trp-Gaba-Cys)-NH₂ Ac-2-Nal-c(Cys-His-D-Phe-Arg- 1172.4 1172.2 95.2Trp-Gaba-Cys)-NH₂ Nle-c(Cys-His-D-Phe-Arg-Trp- 1046.29 1046.4 97.6Gaba-Cys)-NH₂ Phe-c(Cys-His-D-Phe-Arg-Trp- 1080.3 1080 95.8Gaba-Cys)-NH₂ Ac-Nle-c(Cys-3-Pal-D-Phe-Arg- 1099.35 1099.6 96.6Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-Phe- 1075.28 1075.2 99.9Arg-Trp-Cys)-OH Ac-Nle-c(Cys-His-Phe-Arg-D- 1088.32 1088 95.8Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Asp-D-Ala-His-D-Phe- 1183.4 1182.85 99.9Arg-Bal-Ala-Lys)-NH₂ Ac-Nle-c(Asp-His-D-2-Nal-Arg- 1145.33 1145 99.99Trp-Ala-Lys)-NH₂ Ac-Nle-c(Asp-His-D-2-Nal-Arg- 1145.33 1145 99.99Trp-βAla-Lys)-NH₂ Ac-Nle-c(Cys-His-D-2-Nal-Arg- 1138.38 1137.8 99.99Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-His-D-2-Nal-Arg- 1166.44 1166 99Trp-Ahx-Cys)-NH₂ Ac-hPhe-c(Asp-His-D-2-Nal-Arg- 1207.4 1206.9 99Trp-Gaba-Lys)-NH₂ Ac-Cha-c(Asp-His-D-2-Nal-Arg- 1199.42 1198.8 100Trp-Gaba-Lys)-NH₂ Ac-Arg-c(Cys-D-Ala-His-D-Phe- 1117.3 1116.9 95.10Arg-Trp-Cys)-NH₂ Ac-D-Arg-c(Cys-D-Ala-His-D- 1117.33 1116.8 99.2Phe-Arg-Trp-Cys)-NH₂ Ac-D-Arg-c(Cys-D-Ala-His-D- 1145.38 1144.9 96.4Phe-Arg-Trp-Pen)-NH₂ Ac-D-Arg-c(Cys-His-D-Phe-Arg- 1159.41 1158.9 99.9Trp-Gaba-Pen)-NH₂ Ac-Arg-c(Cys-His-D-Phe-Arg- 1159.41 1159.1 99Trp-Gaba-Pen)-NH₂ Ac-Arg-c(Cys-D-Ala-His-D-Phe- 1145.38 1145.1 99Arg-Trp-Pen)-NH₂ Ac-D-Arg-c(Asp-His-D-Phe-Arg- 1138.3 1138.0 98.0Trp-Ala-Lys)-NH₂ Ac-Arg-c(Asp-His-D-Phe-Arg- 1138.3 1138.1 99.0Trp-Ala-Lys)-NH₂

TABLE 1B Calculated Experimental Molecular Molecular Compound WeightWeight Purity Ac-Arg-c(Cys-D-Ala-His-D-2- 1167.39 1167.40 99.9Nal-Arg-Trp-Cys)-NH₂

Example 3: In Vitro Studies

Compounds of the present invention can be and were tested for activityas ligands of one or more of the melanocortin receptors according to thefollowing procedures. One skilled in the art would know that proceduressimilar to those described herein may be used to assay the bindingactivities of the compounds of the invention to melanocortin receptormolecules.

Radioligand Binding Assays

Cellular membranes used for the in vitro receptor binding assays wereobtained from transgenic CHO-K1 cells stably expressing hMC-R receptorsubtypes 1, 3, 4 or 5. The CHO-K1 cells expressing the desired hMC-Rreceptor type were sonicated (Branson® setting 7, approximately 30 sec)in ice-cold 50 mM Tris-HCl at pH 7.4 and then centrifuged at 39,000 gfor 10 minutes at approximately 4° C. The pellets were resuspended inthe same buffer and centrifuged at 50,000 g for 10 minutes atapproximately 4° C. The washed pellets containing the cellular membraneswere stored at approximately −80° C.

Competitive inhibition of [¹²⁵I](Tyr²)-(Nle⁴-D-Phe⁷)α-MSH([¹²⁵I]-NDP-α-MSH, Amersham Biosciences®) binding was carried out inpolypropylene 96 well plates. Cell membranes (1-10 μg protein/well)prepared as described above were incubated in 50 mM Tris-HCl at pH 7.4containing 0.2% bovine serum albumin (BSA), 5 mM MgCl₂, 1 mM CaCl₂ and0.1 mg/mL bacitracin, with increasing concentrations of the testcompound and 0.1-0.3 nM [¹²⁵I]-NDP-α-MSH for approximately 90-120minutes at approximately 37° C. Bound [¹²⁵I]-NDP-α-MSH ligand wasseparated from free [¹²⁵I]-NDP-α-MSH by filtration through GF/C glassfiber filter plates (Unifilter®; Packard) presoaked with 0.1% (w/v)polyethylenimine (PEI), using a Packard Filtermate® harvester. Filterswere washed three times with 50 mM Tris-HCl at pH 7.4 at a temperatureof approximately 0-4° C. and then assayed for radioactivity using aPackard Topcount® scintillation counter. Binding data were analyzed bycomputer-assisted non-linear regression analysis (XL fit; IDBS).

A selection of the preferred embodiments was tested using theabove-discussed assay and the binding constants (Ki in nM) are reportedin Tables 2A, 2B and 2C.

TABLES 2A, 2B and 2C—Radioligand Binding Assay Data for SelectedCompounds

TABLE 2A Ki Ki Ki Ki Ki hMC1-R/ Compound hMC1-R hMC3-R hMC4-R hMC5-RMC4-R Ac-Arg-c(Cys-D-Ala-His-D- 3.87 10.1 2.09 430 1.9Phe-Arg-Trp-Cys)-NH₂ Ac-D-Arg-c(Cys-D-Ala-His-D- 4.01 12.1 1.76 352 2.3Phe-Arg-Trp-Cys)-NH₂ Ac-D-Arg-c(Cys-D-Ala-His-D- 8.29 13.3 2.78 816 3.0Phe-Arg-Trp-Pen)-NH₂ Ac-D-Arg-c(Cys-His-D-Phe- 3.93 172 11.0 538 0.36Arg-Trp-Gaba-Pen)-NH₂ Ac-Arg-c(Cys-His-D-Phe-Arg- 1.81 20.5 4.57 502 0.4Trp-Gaba-Pen)-NH₂ Ac-Arg-c(Cys-D-Ala-His-D- 9.67 22.0 4.2 1900 2.3Phe-Arg-Trp-Pen)-NH₂ Ac-D-Arg-c(Asp-His-D-Phe- 0.79 45.5 1.21 493 0.6Arg-Trp-Ala-Lys)-NH₂ Ac-Arg-c(Asp-His-D-Phe-Arg- 0.68 20.7 1.01 783 0.7Trp-Ala-Lys)-NH₂

TABLE 2B Ki Ki Ki Ki Ki hMC1-R/ Compound hMC1-R hMC3-R hMC4-R hMC5-RMC4-R Ac-Nle-c(Cys-D-Ala-His-D-2- 114 63.9 3.07 1657 37.1Nal-Arg-1-Nal-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 11 26 7.6 1800 1.4Phe-Arg-Trp-Cys)-NH₂ D-Phe-c(Cys-His-D-(Et)Tyr- 0.05 9.3 1.1 2.9 0.0Arg-Trp-β-Ala-D-Cys)-Thr-NH₂ Nle-c(Cys-His-D-Phe-Arg-Trp- 0.07 4.1 0.858.8 0.1 Apn-Cys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg- 0.12 10 0.43 0.42 0.3Trp-Gaba-Pen)-NH₂ Nle-c(Cys-His-D-Phe-Arg-Trp- 0.05 1.3 0.47 0.2 0.1Gaba-Cys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg- 0.0996 9318 0.617 10.9 0.16Trp-β-Ala-Lys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg- .0132 16.1 1.23 0.3590.11 Trp-Ahx-Cys)-NH₂ D-Phe-c(Cys-His-D-Phe-Arg- 0.207 43.2 2.58 3440.08 Trp-β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-Phe-Arg- 0.420 106 4.751260 0.09 Trp-Gaba-D-Cys)-Thr-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg- 0.09519.33 0.894 13.4 0.11 Trp-Apn-Cys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg- 0.999300 11.1 431 0.09 Trp-Apn-Lys)-NH₂ Ac-Cha-c(Asp-His-D-Phe-Arg- 0.10611.8 1.49 110 0.07 Trp-Gaba-Lys)-NH₂ Ac-Nle-c(Asp-His-D-Phe-Arg- 0.05069.89 1.04 16.3 0.05 Trp-Gaba-Lys)-NH₂ Ac-Chg-c(Asp-His-D-Phe-Arg- 0.884223 22.5 609 0.04 Trp-Gaba-Lys)-NH₂ Ac-hCha-c(Asp-His-D-P-he- 0.721 93.556.0 747 0.01 Arg-Trp-Gaba-Lys)-NH₂ Ac-D-Chg-c(Asp-His-D-Phe- 0.227 14.52.99 164 0.08 Arg-Trp-Gaba-Lys)-NH₂ Ac-hPhe-c(Asp-His-D-Phe-Arg- 0.27725.2 3.37 203 0.08 Trp-Gaba-Lys)-NH₂ Ac-Nle-c(Cys-His-D-Phe-Arg- 0.32314.1 1.96 24.0 0.16 D-Trp-β-Ala-Cys)-NH₂ Ac-Nle-c(Pen-D-Ala-His-D- 34.1118 17.0 5560 2.01 Phe-Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 29.122.8 3.84 2550 7.58 Phe-Arg-Trp-Pen)-NH₂ D-Phe-c(Cys-His-D-Phe-hArg-0.442 123 10.3 521 0.04 Trp-β-Ala-D-Cys)-Thr-NH₂D-Phe-c(Cys-His-D-Phe-Arg- 5.80 3370 583 1130 0.01Bip-β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-(Et)Tyr- 0.0567 31.4 14.79.27 0 hArg-Trp-β-Ala-D-Cys)-Thr- NH₂ D-Phe-c(Cys-His-D-Phe-hArg- 1.681260 172 1220 0.01 Bip-β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D-(Et)Tyr-0.128 85.6 36.9 38.0 0 hArg-Bip-β-Ala-D-Cys)-Thr- NH₂Ac-Nle-c(Cys-D-Ala-His-D- 0.352 149 3.01 339 0.12Phe-Arg-Trp-Gly-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 3.93 876 48.0 49400.08 Phe-Arg-Trp-D-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 0.995 287 4.80766 0.21 Phe-Arg-Trp-β-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 0.848 1843.76 956 0.23 Phe-Arg-Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 1.10228 7.58 859 0.15 Phe-Arg-Trp-Apn-Cys)-NH₂ Ac-Nle-c(Asp-D-Ala-His-D-0.659 98.9 2.55 4.19 0.26 Phe-Arg-Trp-Lys)-NH₂ Ac-Nle-c(Asp-D-Ala-His-D-4.12 445 50.6 4300 0.08 Phe-Arg-Bal-Lys)-NH₂ Ac-c(Cys-Glu-His-D-Phe-Arg-111 1710 47.7 694 2.33 Trp-Ala-Cys)-NH₂ Ac-c(Cys-Glu-His-D-Phe-Arg- 2622500 96.4 1460 2.72 2-Nal-Ala-Cys)-NH₂ Ac-c(Cys-D-Ala-His-D-Phe- 1995990 96.7 >10000 2.06 Arg-Trp-Ala-Cys)-NH₂ Ac-c(Cys-D-Ala-His-D-Phe- 1324560 40.7 8810 3.24 Arg-2-Nal-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-9.12 1130 22.1 2860 0.41 Phe-Arg-Trp-Ala-Cys)-NH₂Ac-Nle-c(Cys-D-Ala-His-D- 1.00 227 5.55 496 0.18Phe-Arg-Trp-β-Ala-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 0.536 169 3.12 3580.17 Phe-Arg-Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 32.1 330 17.4165 1.84 Phe-Arg-Trp-Pen)-OH Ac-Nle-c(Cys-D-Abu-His-D- 10.6 41.1 7.6954.9 1.38 Phe-Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Val-His-D- 13.0 104 10.140 1.29 Phe-Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Ile-His-D-Phe- 4.28 38.5 9.012.5 0.48 Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Leu-His-D- 1.60 6.82 4.13 5.570.39 Phe-Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Tle-His-D-Phe- 12.0 85.8 11.240 1.07 Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Cha-His-D- 0.353 2.08 1.41 0.8570.25 Phe-Arg-Trp-Cys)-NH₂ Ac-Nle-c(Pen-His-D-Phe-Arg- 0.537 86.1 5.892.56 0.09 Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Pen-His-D-Phe-Arg- 0.744 178 3.512.69 0.21 Trp-Gaba-Pen)-NH₂ Ac-Leu-c(Cys-His-D-Phe-Arg- 0.216 17.4 0.9950.486 0.22 Trp-Gaba-Cys)-NH₂ Ac-Cha-c(Cys-His-D-Phe-Arg- 0.107 9.110.884 0.354 0.12 Trp-Gaba-Cys)-NH₂ Ac-Ile-c(Cys-His-D-Phe-Arg- 0.14813.9 1.06 0.423 0.14 Trp-Gaba-Cys)-NH₂ Ac-Phe-c(Cys-His-D-Phe-Arg- 0.25418.5 2.13 0.714 0.12 Trp-Gaba-Cys)-NH₂ Ac-Val-c(Cys-His-D-Phe-Arg- 0.25629.9 1.98 0.864 0.13 Trp-Gaba-Cys)-NH₂ Ac-2-Nal-c(Cys-His-D-Phe- 0.56039.2 2.94 2.73 0.19 Arg-Trp-Gaba-Cys)-NH₂ Phe-c(Cys-His-D-Phe-Arg-Trp-0.186 15.2 4.93 0.537 0.04 Gaba-Cys)-NH₂ Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-21.1 151 10.4 92.6 2.03 Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D- 30.7152 15.6 114 1.97 Phe-Arg-Trp-Cys)-OH Ac-Nle-c(Cys-His-Phe-Arg-D- 5.20150 138 20.3 0.04 Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Asp-D-Ala-His-D- 4.89 29021.3 11.1 0.23 Phe-Arg-Bal-Ala-Lys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-2- 25.53.82 7.61 102 3.35 Nal-Arg-Trp-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-2- 32.55.85 2.53 94.6 12.85 Nal-Arg-2-Nal-Cys)-NH₂ Ac-Nle-c(Cys-D-Ala-His-D-2-22.2 12.7 16.6 125 1.34 Nal-Arg-Bal-Cys)-NH₂ Ac-Nle-c(Asp-His-D-2-Nal-1.17 1.56 0.277 3.24 4.22 Arg-Trp-Ala-Lys)-NH₂ Ac-Nle-c(Asp-His-D-2-Nal-0.648 2.78 0.329 1.4 1.97 Arg-Trp-β-Ala-Lys)-NH₂Ac-Nle-c(Cys-His-D-2-Nal-Arg- 0.393 1.86 0.375 1.11 1.05Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-His-D-2-Nal-Arg- 0.333 2.91 0.998 0.3660.33 Trp-Ahx-Cys)-NH₂ Ac-hPhe-c(Asp-His-D-2-Nal- 0.461 2.45 0.931 1.370.50 Arg-Trp-Gaba-Lys)-NH₂ Ac-Cha-c(Asp-His-D-2-Nal- 0.576 3.98 2.823.91 0.20 Arg-Trp-Gaba-Lys)-NH₂

TABLE 2C Ki Ki Ki Ki Ki hMC1-R/ Compound hMC1-R hMC3-R hMC4-R hMC5-RMC4-R Ac-Arg-c(Cys-D-Ala-His-D-2- 17.9 1.68 0.256 23.4 69.9Nal-Arg-Trp-Cys)-NH₂Cyclic AMP Bioassay

Intracellular cyclic AMP (cAMP) levels were determined by anelectrochemiluminescence (ECL) assay (Meso Scale Discovery®,Gaithersburg, Md.; referred to hereinafter as MSD). CHO-K1 cells stablyexpressing the hMC receptor subtypes were suspended in RMPI 1640® assaybuffer (RMPI 1640 buffer contains 0.5 mM isobutylmethylxanthine (IBMX),and 0.2% protein cocktail (MSD blocker A)). Transgenic CHO-K1 cellsstably expressing hMC receptor subtypes 1, 3, 4 or 5 were dispensed at adensity of approximately 7,000 cells/well in 384-well Multi-Array®plates (MSD) containing integrated carbon electrodes and coated withanti-cAMP antibody. Increasing concentrations of the test compounds wereadded and the cells were incubated for approximately 40 minutes atapproximately 37° C. Following this incubation, lysis buffer(HEPES-buffered saline solution with MgCl₂ and Triton X-100® at ph 7.3)containing 0.2% protein cocktail and 2.5 nM TAG™ ruthenium-labeled cAMP(MSD) was added and the cells were incubated for approximately 90minutes at room temperature. At the end of the second incubation periodread buffer (Tris-buffered solution containing an ECL co-reactant andTriton X-100 at ph 7.8) was added and the cAMP levels in the celllysates were immediately determined by ECL detection with a SectorImager 6000 Reader® (MSD). Data were analyzed using a computer-assistednon-linear regression analysis (XL fit; IDBS) and reported as either anEC₅₀ value or a Kb value.

EC₅₀ represents the concentration of an agonist compound needed toobtain 50% of the maximum reaction response, e.g., 50% of the maximumlevel of cAMP as determined using the assay described above. The Kbvalue reflects the potency of an antagonist and is determined by Schildanalysis. In brief, concentration-response curves of an agonist arecarried out in the presence of increasing concentrations of anantagonist. The Kb value is the concentration of antagonist which wouldproduce a 2-fold shift in the concentration-response curve for anagonist. It is calculated by extrapolating the line on a Schild plot tozero on the y-axis.

A selection of compounds was tested using the above-discussed assays andthe results are reported in Tables 3A, 3B, 3C, and 3D.

TABLES 3A, 3B, 3C, and 3D—cAMP Bioassay Data for Selected Compounds

TABLE 3A EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ hMC1-R/ Compound hMC1-R hMC3-R hMC4-RhMC5-R MC4-R Ac-Arg-c(Cys-D-Ala-His- 5.79 5.25 0.313 1630 18.0D-Phe-Arg-Trp-Cys)- NH₂ Ac-D-Arg-c(Cys-D-Ala- 6.17 5.6 0.397 1020 16.0His-D-Phe-Arg-Trp-Cys)- NH₂ Ac-D-Arg-c(Cys-D-Ala- 26.5 10.5 0.493 244054.0 His-D-Phe-Arg-Trp-Pen)- NH₂ Ac-D-Arg-c(Cys-His-D- 8.43 32.4 0.9592140 9.0 Phe-Arg-Trp-Gaba-Pen)- NH₂ Ac-Arg-c(Cys-His-D- 4.23 8.09 0.71923.2 6.0 Phe-Arg-Trp-Gaba-Pen)- NH₂ Ac-Arg-c(Cys-D-Ala-His- 48.3 13.30.79 10000 61.0 D-Phe-Arg-Trp-Pen)- NH₂ Ac-D-Arg-c(Asp-His-D- 1.48 5.760.078 297 19.0 Phe-Arg-Trp-Ala-Lys)- NH₂ Ac-Arg-c(Asp-His-D- 1.39 2.890.055 467 25.0 Phe-Arg-Trp-Ala-Lys)- NH₂ ND = not determined

TABLE 3B EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ hMC1-R/ Compound hMC1-R hMC3-R hMC4-RhMC5-R MC4-R Ac-Nle-c(Cys-D-Ala-His- 2.4 0.33 0.078 420 31D-Phe-Arg-Trp-Cys)- NH₂ D-Phe-c(Cys-His-D- 0.35 1.1 0.11 0.37 3(Et)Tyr-Arg-Trp-β-Ala- D-Cys)-Thr-NH₂ Nle-c(Cys-His-D-Phe- 0.31 0.270.018 3.1 17 Arg-Trp-Apn-Cys)-NH₂ Ac-Nle-c(Cys-His-D-Phe- 0.28 0.240.028 3.9 10 Arg-Trp-Gaba-Pen)-NH₂ Nle-c(Cys-His-D-Phe- 0.37 0.1 0.0211.7 18 Arg-Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Asp-His-D- 0.834 0.145 0.128 2.796.52 Phe-Arg-Trp-β-Ala-Lys)- NH₂ Ac-Nle-c(Cys-His-D-Phe- 0.76 0.1990.0492 1.73 15.45 Arg-Trp-Apn-Cys)-NH₂ Ac-Cha-c(Asp-His-D- 3.26 0.1890.0949 30.2 34.35 Phe-Arg-Trp-Gaba-Lys)- NH₂ Ac-Nle-c(Asp-His-D- 1.370.628 0.131 3.48 10.46 Phe-Arg-Trp-Gaba-Lys)- NH₂ Ac-hCha-c(Asp-His-D-2.27 3.32 7.24 415 0.31 Phe-Arg-Trp-Gaba-Lys)- NH₂Ac-Nle-c(Pen-D-Ala-His- ND 1.89 0.531 ND ND D-Phe-Arg-Trp-Cys)- NH₂Ac-Nle-c(Cys-D-Ala-His- 14.3 2.03 0.183 2240 78.14 D-Phe-Arg-Trp-Pen)-NH₂ D-Phe-c(Cys-His-D- 0.345 2.71 5376 2.38 0.06 (Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂ D-Phe-c(Cys-His-D- 0.685 81.8 86.9 31.8 0.01(Et)Tyr-hArg-Bip-β-Ala- D-Cys)-Thr-NH₂ Ac-Nle-c(Asp-D-Ala-His- 0.9313.22 1.65 >10000 0.56 D-Phe-Arg-Bal-Lys)-NH₂ Ac-Nle-c(Cys-D-Leu-His-3.24 0.465 0.0915 78.5 35.41 D-Phe-Arg-Trp-Cys)- NH₂ Ac-Nle-c(Cys-D-Cha-0.819 0.541 0.453 45.3 1.81 His-D-Phe-Arg-Trp-Cys)- NH₂ ND = notdetermined

TABLE 3C EC50 Kb Kb EC50 Compound hMC1-R hMC3-R MC4-R hMC5-RAc-Nle-c(Cys-D-Ala-His- 17.6 12.4 38.8 11.8 D-2-Nal-Arg-Trp-Cys)- NH₂Ac-Nle-c(Asp-His-D-2- 0.619 2.98 0.109 0.189 Nal-Arg-Trp-Ala-Lys)- NH₂Ac-Nle-c(Asp-His-D-2- 0.913 0.536 0.346 0.489 Nal-Arg-Trp-β-Ala-Lys)-NH₂ Ac-Nle-c(Cys-His-D-2- 0.231 18.4 0.782 0.153 Nal-Arg-Trp-Gaba-Cys)-NH₂ Ac-Nle-c(Cys-His-D-2- 0.581 10.8 0.967 0.126 Nal-Arg-Trp-Ahx-Cys)-NH₂ Ac-hPhe-c(Asp-His-D-2- 0.413 9.32 0.824 0.307 Nal-Arg-Trp-Gaba-Lys)-NH₂ Ac-Cha-c(Asp-His-D-2- 1.27 3.02 0.442 0.736 Nal-Arg-Trp-Gaba-Lys)-NH₂ Ac-Nle-c(Cys-D-Ala-His- 383 61.5 53.6 2842 D-2-Nal-Arg-l-Nal-Cys)-NH₂

TABLE 3D EC50 Kb Kb EC50 Compound hMC1-R hMC3-R MC4-R hMC5-RAc-Arg-c(Cys-D-Ala-His- 193 5.72 1.58 1111 D-2-Nal-Arg-Trp-Cys)- NH₂

Example 4: In Vivo Studies

Compounds of the present invention can be and were tested for an effectupon food intake and/or body weight according to the followingprocedures. One skilled in the art would know that procedures similar tothose described herein may be used to assay the effect of the compoundsof the invention upon food intake and/or body weight.

Ligand compounds activating melanocortin receptors tested in the in vivostudies were as follows (Table 4):

TABLE 4 Ligand Code Structure Compound AAc-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Compound BAc-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂ Compound CAc-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂ Compound DD-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D- Cys)-Thr-NH₂ Compound EAc-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Compound FAc-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Compound GAc-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂Acute Feeding Experiments (Fasting)

Male Sprague Dawley rats (250 g) were housed in individual cages andmaintained under 12:12 hour light:dark conditions. The rats were fastedfor 18 hours prior to the start of the experiment with water availablead libitum. At time 0, the rats were injected subcutaneously (sc) withselected compounds at doses of either 500 or 100 nmole/kg, or withvehicle, and were provided with food. Individual food consumption wasmeasured at about 1, 2, 3, 4, 5 and 6 hours after injection. Data forselected compounds of the invention are reported in FIGS. 1A and 1B.

Acute Feeding Experiments (Non Fasting)

Male Sprague Dawley rats (250 g) are housed in individual cages andmaintained under 12:12 hour light:dark conditions. Food and water isavailable ad libitum throughout the experiment. At time 0, the rats areinjected sc with compound at doses of either 500 or 100 nmole/kg, orwith vehicle. Individual food consumption is measured at about 1, 2, 3,4, 5 and 6 hours after injection.

Chronic Feeding Experiments

Male Sprague Dawley rats (250 g) were housed in individual cages andmaintained under 12:12 hour light:dark conditions with both food andwater available ad libitum. The rats were injected sc 3×/day(approximately 0800 hour, 1200 hour, and 1600 hour) with compound atvarious doses or with vehicle for 7 days. Individual body weight andfood consumption were measured daily. Data for selected compounds of theinvention are reported in FIGS. 2A and 2B, FIGS. 3A and 3B, and FIGS. 4Aand 4B.

Administration and Use

The peptides of this invention can be provided in the form ofpharmaceutically acceptable salts. Examples of such salts include, butare not limited to, those formed with organic acids (e.g., acetic,lactic, maleic, citric, malic, ascorbic, succinic, benzoic,methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids(e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), andpolymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic,polyglycolic, or copolymers of polylactic-glycolic acids). A typicalmethod of making a salt of a peptide of the present invention is wellknown in the art and can be accomplished by standard methods of saltexchange. Accordingly, the TFA salt of a peptide of the presentinvention (the TFA salt results from the purification of the peptide byusing preparative HPLC, eluting with TFA containing buffer solutions)can be converted into another salt, such as an acetate salt, bydissolving the peptide in a small amount of 0.25 N acetic acid aqueoussolution. The resulting solution is applied to a semi-prep HPLC column(Zorbax®, 300 SB, C-8). The column is eluted with: (1) 0.1N ammoniumacetate aqueous solution for 0.5 hours; (2) 0.25N acetic acid aqueoussolution for 0.5 hours; and (3) a linear gradient (20% to 100% ofsolution B over 30 minutes) at a flow rate of 4 ml/min (solution A is0.25N acetic acid aqueous solution; solution B is 0.25N acetic acid inacetonitrile/water, 80:20). The fractions containing the peptide arecollected and lyophilized to dryness.

As is well known to those skilled in the art, the known and potentialuses of peptides with melanocortin receptor (MC-R) agonist or antagonistactivity is varied and multitudinous, thus the administration of thecompounds of this invention for purposes of eliciting an agonist effectcan have the same effects and uses as melanocortin itself.

Accordingly, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of formula (I) in association with apharmaceutically acceptable carrier.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment. In general, aneffective dosage for the activities of this invention is in the range of1×10⁻⁷ to 200 mg/kg/day, preferably 1×10⁻⁴ to 100 mg/kg/day which can beadministered as a single dose or divided into multiple doses.

The compounds of this invention can be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous or subcutaneousinjection, or implant), nasal, vaginal, rectal, sublingual or topicalroutes of administration and can be formulated with pharmaceuticallyacceptable carriers to provide dosage forms appropriate for each routeof administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than suchinert diluents, e.g., lubricating agents such as magnesium stearate. Inthe case of capsules, tablets and pills, the dosage forms may alsocomprise buffering agents. Tablets and pills can additionally beprepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, the elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. Preparations may be sterilized by,for example, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. Preparations can alsobe manufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as cocoa butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

Further, a compound of this invention can be administered in a sustainedrelease composition such as those described in the following Patents andPatent applications. U.S. Pat. No. 5,672,659 teaches sustained releasecompositions comprising a bioactive agent and a polyester. U.S. Pat. No.5,595,760 teaches sustained release compositions comprising a bioactiveagent in a gelable form. U.S. Pat. No. 5,821,221 teaches polymericsustained release compositions comprising a bioactive agent andchitosan. U.S. Pat. No. 5,916,883 teaches sustained release compositionscomprising a bioactive agent and cyclodextrin. The teachings of theforegoing Patents and applications are incorporated herein by reference.

What is claimed is:
 1. A compound selected from the group consisting of:D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:24);D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:3);D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH₂ (SEQ ID NO:3);D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:23);D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:24);D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:26);D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:25);D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:26); andAc-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂ (SEQ ID NO:11); or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein the compound isD-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:25) or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 1, wherein the compound isD-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO: 26) or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1, wherein the compound isD-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:26)or a pharmaceutically acceptable salt thereof.
 5. A compound accordingto claim 1, wherein the compound isD-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂ (SEQ ID NO:24)or a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 1, wherein the compound isAc-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO:11) or apharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.
 8. A method of treatinga metabolic disease or medical condition accompanied by weight gain,comprising administering to a subject in need thereof a therapeuticallyeffective amount of compound of claim
 1. 9. The method of claim 8,wherein the disease or condition is selected from obesity, feedingdisorders, Prader-Willi Syndrome, or diabetes.